Immunol Res (2013) 57:5269

DOI 10.1007/s12026-013-8462-3

IMMUNOLOGY & MICROBIOLOGY IN MIAMI

The immune system and head and

neck squamous cell carcinoma:
from carcinogenesis to new
therapeutic opportunities
Monika E. Freiser Paolo Serafini Donald T. Weed
Monika E. Freiser Paolo Serafini Donald T. Weed

Published online: 12 November 2013

Springer Science+Business Media New York 2013

Abstract Head and neck squamous cell carcinomas (HNSCCs) exhibit complex interactions with the host immune
system that may simultaneously explain resistance to various therapeutic modalities and that may also provide opportu-
nities for therapeutic intervention. Discoveries in immunologic research over the last decade have led to an increased
understanding of these interactions as well as the development of a multitude of investigational immunotherapies. Here, we
describe the interaction between HNSCC and the immune system, including a discussion of immune cells involved with
tumor carcinogenesis and the role of immune-modulating factors derived from tumors. We also describe the current
immunotherapeutic approaches being investigated for HNSCC, including a discussion of the successes and limitations.
With this review, we hope to present HNSCC as a model to guide future research in cancer immunology.

Keywords Head and neck squamous cell carcinoma
Immunosuppression
Immunotherapy
Tumor vaccines
Antibody
therapies
Human papilloma virus

Introduction fatality rate remains high, with about 56 % of patients

Head and neck squamous cell carcinomas (HNSCCs) rep-
resent about 95 % of tumors originating from the epithe-
lium of the upper aerodigestive tract and globally account
for the sixth most common malignancy [1]. Over 634,000
new cases were reported worldwide in 2008, and the case
P. Serafini (&)
Department of Microbiology and Immunology, University of
Miami Miller School of Medicine, RMSB 3075, 1600 NW 10th
Avenue, Miami, FL 33136, USA
e-mail: pserafini@med.miami.edu
D. T. Weed (&)
Division of Head and Neck Surgery, Department of
Otolaryngology, University of Miami Miller School of
Medicine, 1475 NW 12th Avenue, 3rd Flr, Suite 3550, Miami,
FL 33136, USA
e-mail: dweed@med.miami.edu
M. E. Freiser
University of Miami Miller School of Medicine, 1475 NW 12th
Avenue, 3rd Flr, Suite 3550, Miami, FL 33136, USA
e-mail: mfreiser@med.miami.edu
dying from their disease [2]. This speaks to the limitations
in treatment efficacy of the currently available standard of
care treatment options employing combinations of surgery,
radiotherapy, and chemotherapy. These limitations high-
light a need for new therapeutic modalities and approaches
in HNSCC, a need that is being met by an expanding role
for immunotherapy as a fourth treatment option for this
disease. Much has been discovered about the interaction of
the immune system and HNSCC tumors, both in the
development of the disease and in the mechanisms of
tumor resistance. Understanding this interaction is essential
to developing successful immunotherapeutic interventions.
Interaction between HNSCC and the immune system
The immune system is intimately involved in the process of
HNSCC carcinogenesis (Fig. 1a). Ideally, when an epi-
thelial cell acquires a deleterious mutation that cannot be
repaired, it should undergo apoptosis [3]. When this fails,
the immune system should recognize the cell as abnormal

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Immunology & Microbiology in Miami (2013) 57:5269
Fig. 1 The interaction between immune system and HNSCC. a
Anatomical location of HNSCC. The micro- and macro-environment
of HNSCC is characterized by different immunological components
that include lymph nodes, tonsils, resident immune cells of the
mucosa (i.e., Langerhans cells), and immune-stimulatory elements
(i.e., oral bacteria). b Schematic diagram of the interactions between
HNSCC and the immune system. Langerhans cells and resident
myeloid DCs or DCs infiltrating the mucosa uptake the tumor
antigens (1) and migrate (2) to the draining lymph nodes to cross-
present them to the effector T cells (3). Once activated, T cells move
and attack it accordingly; this concept of immune system
recognition and elimination of transformed cells is known
as immunosurveillance, first introduced in 1970 by Burnet
and Thomas [4, 5]. However, there is a failure of this
paradigm with all clinically evident cancers, and growing
evidence demonstrates that certain immune cells may in
fact promote the development and survival of neoplastic
cells.
Perhaps the most basic evidence of a relationship
between HNSCC and the immune system is that immu-
nodeficiency increases HNSCC risk [6]. For example,
premalignant leukoplakia develops in 13 % of renal
transplant patients as compared to 0.6 % of age- and sex-
matched individuals, and about 10 % will become frank
HNSCC [7, 8]. Increased incidence of HNSCC has been
observed in bone marrow transplant patients [911] and
HIV-positive patients [12]. While HNSCC is not an AIDS-
defining illness, HIV-positive patients develop HNSCC
earlier in life with more advanced disease and poorer
prognosis [13]. As significant as immunodeficiency may be
in HNSCC risk elevation, most patients have normal
immune systems when the cancer develops. In the immu-
nocompetent patient, the process to blame is immunoedit-
ing [14].
53
back to the tumor where they exert their tumoricidal action (4). To
counteract the immune surveillance, neoplastic cells are edited to be
ignored, to directly inhibit T-cell activity, or to secrete tumor-derived
factors (TDF) that inhibit DC migration to the lymph nodes (5a) and
alter the myelopoiesis (5b) inducing the generation of MDSCs and
Tregs. These cells inhibit the immune surveillance (6) by inhibiting
DC maturation and migration, by preventing T-cell expansion, by
directly inhibiting the effector function of T cells or by promoting
T-cell anergy
Immunoediting selects for tumor cells
Immunoediting is a concept first introduced by Dunn and
Schreiber in 2002 [5, 15] that describes how tumor cells
develop in the setting of a healthy immune system. Cancer
immunoediting is composed of three processes: elimina-
tion, equilibrium, and escape. Immunosurveillance occurs
during the elimination process, whereby the immune sys-
tem recognizes transitioned cells and induces cell death
through various mechanisms. Most preclinical lesions are
likely cleared this way [15]. Of note, aerodigestive epi-
thelial cells encounter foreign particles and bacteria more
often than many tissues, and yet most patients do not suffer
from perpetual mucosal inflammation. This natural ten-
dency for tolerance may predispose to tolerance toward
transitioned cells [16]. Those transitioned cells that are
capable of surviving initially enter into the equilibrium
phase, whereby Darwinian pressures continue to select for
the tumor cells that develop mutations allowing continued
survival. The escape process occurs once a tumor cell has
the means to efficiently overcome the immune system.
These three processes may co-exist in a collection of tumor
cells. By the time a tumor becomes clinically evident,
immunoediting has already selected for the cells that are
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best suited to survive in an immunologically intact
environment.
Mechanisms of immune system escape
There are four main ways that selective pressures during
the equilibrium process are thought to lead to HNSCC
escape in immunocompetent patients: tumor cell evasion of
detection, tumor resistance to attack, direct tumor cell
inhibition of local immune function, and indirect inhibition
of immune function by way of recruitment of immuno-
suppressive players [16]. While evidence exists supporting
all four, it is now clear that selection of malignant cells
with direct or indirect intrinsic immunosuppressive activity
is particularly common.
HNSCC cells evade immune system detection
Head and neck squamous cell carcinoma cells may trick the
immune system into disregarding them as normal cells.
This can be achieved by decreasing the expression of
surface MHC class I molecules [17] or by impairing their
antigen processing machinery [16]. HNSCC may also lose
immune-dominant epitopes during immunoediting [6].
However, immune system evasion is not thought to play a
large role as most HNSCC tumors have abnormal antigens
that are recognized by the immune system even though the
immune system does not effectively react. Lists detailing
many of these tumor-associated antigens (TAAs) have been
published recently [16, 1821]. In many cases, the specific
CD8? T-cell targeting the TAA is actually present in the
patient. Furthermore, patients TAA-specific CD8? T cells
that are expanded in vitro and exposed to autologous tumor
cells can lyse the tumor cells when incubated with stimu-
latory factors like IFN-c [6].
HNSCC cells resist immune attack
Head and neck squamous cell carcinoma tumors may
express receptors typically found on immune cells that
induce anti-apoptotic pathways [6]. One such receptor is
toll-like receptor 4 (TLR-4), which normally binds to
lipopolysaccharide, found on bacteria. TLR-4 typically
helps protect immune cells during natural killer (NK) cell
attack, and on tumor cells may allow them to resist NK-
induced apoptosis [22].
HNSCC cells express or secrete factors that directly inhibit
the immune system
As is the case with many cancers, most HNSCC tumors
express or secrete factors that directly inhibit the immune
system in the microenvironment. A number of apoptosis-
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promoting factors have been identified in HNSCC,
including Galectin-1 [23], FASL [24, 25], TRAIL, and
PDL-1 [26]. These factors expressed by the malignant cells
seem to induce T-cell apoptosis when binding to the cog-
nate receptor. A factor commonly present in human pap-
illoma virus positive (HPV?) HNSCC cells is PDL-1,
which binds with PD-1 on the T cells and promotes anergy,
exhaustion, or apoptosis [27, 28]. Direct inhibition of local
T cells by tumor cells is not the only immunosuppressive
strategy present. Indeed, it is becoming clear that HNSCC
cells can promote an aberrant hematopoiesis that affects the
entire immune system.
HNSCC cells indirectly inhibit the immune system by
recruiting and directing an army of pro-tumoral cells
It is now evident that HNSCC tumors secrete factors that
alter normal hematopoiesis and induce the production and
recruitment of cells from the innate and adaptive immune
system to effectively counter and silence their anti-tumoral
counterparts. These cells are part of a network of cells
modulated by HNSCC tumors. It is important to understand
this network in order to best design immunotherapeutic
strategies.
Cellular network of immune modulation in HNSCC
The HNSCC microenvironment usually contains a signifi-
cant amount of non-cancerous stromal cells in addition to
neoplastic cells; these include tumor-associated macro-
phages (TAMs), myeloid derived suppressor cells
(MDSCs), immature dendritic cells (iDCs), and various
types of T cells (Fig. 1b). These immune cells are not
innocent bystanders; indeed, they play an important role in
disease outcome. Depending on the composition and acti-
vation status of these cells and the surrounding signaling
factors, the net effect can be either favorable or detrimental
to tumor progression and metastasis. Table 1 summarizes
the involvement of specific stromal cells and the net
immunosuppressive effect.
Effector T cells
Cell-mediated immunity is considered to be the most
important process for antitumor immunity; intact CD8?
CD4? T helper 1 (Th1) function is essential for effective
immunosurveillance and tumor containment [4, 14]. As
mentioned above, tumor antigen-specific CD8? T cells
have been identified in patients, yet these cells are unable
to fully perform their tumoricidal action because of a
suppressive network orchestrated by the tumor [6]. HNSCC
patients have fewer lymphocytes in their blood [29] but a
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Table 1 Cellular network of immune modulation specimen correlates with better survival in HNSCC
Cell Involvement Net effect
patients [3133]. Nevertheless, defects are commonly
found in the effector cells of patients with HNSCC. Even
Cytotoxic T Recognize tumor CD8? T cells system after curative resection of HNSCC cancers, patients have
cells (CD8?) antigens but are impairment [36]
reduced T-cell counts for several years [34]. Circulating
suppressed
CD8? T cells in the blood of most HNSCC patients have
Helper T cells T helper 1 suppressed, T Humoral response
(CD4?) helper 2 favored; T favored, which is an increased ratio of pro-apoptotic protein BAX to anti-
helper 2 cells express ineffective against apoptotic factor Bcl-2 [25]. Intrinsic molecular defects are
IL-4, IL-10, IL-13 tumor; cytotoxic detectable in the T cells, including downregulation of the
activity inhibited [16] n-chain of the CD3 complex, a low responsiveness to IL-2
Natural killer NKG2D internalized, Failure to destroy tumor [35], and a reduced proliferative capability to mitogenic
cells inhibitory receptors cells [36, 38]
activated, reduced stimulation [36].
expression of
cytotoxic substances, Natural killer cells
decreased CD1d-
restricted NK T cells
Natural killer cells of the innate immune system typically
Dendritic cells Impaired maturation; Tolerogenic
immature DCs lack environment; partake in immunosurveillance and antitumor immunity
sufficient CD80 and insufficient T-cell [37]. While NK cells should be able to clear tumor cells
CD86 to co-stimulate; stimulation [48, 80] with decreased MHC class I expression and perform anti-
promote T regulatory body-dependent cellular cytotoxicity, successful HNSCC
cell proliferation
cells inhibit NK function [36]. NK cell cytotoxicity
Tumor- M2 phenotype; produce Impairs T helper
associated IL-10 TGF-b, VEGF; 1/CD8? pathway and
depends on the relative stimulation of activating versus
macrophages secrete remodeling instead promotes inhibitory receptors: tumor cells ensure that inhibitory
(TAMs) proteases production of Treg signals dominate [38]. In addition, through secretion of
cells; contributes to TGF-b1 and a soluble form of MHC-I-related chain, tumor
tumor stabilization
and angiogenesis [49]
cells cause reduced expression of the activating receptors
Myeloid Produce TGF-b, Severe cytotoxic T-cell
NKG2D and CD16 [36, 39]. Tumor cells resist NK attack
derived peroxynitrite; induce dysfunction [58] by the production of anti-apoptotic molecules [22].
suppressor local L-arginine HNSCC patients have severe reductions in their circulating
cells starvation; Secrete CD1d-restricted NK T (iNKT) cells [40], which are
(MDSCs) remodeling proteases
important for activating effector cells [36].
Regulatory T Secrete TGF-b, IL-10; T-cell anergy or death
cells (Tregs) induce local and APC cell
tryptophan starvation dysfunction [36] Dendritic cells
Cytokine Imbalanced toward T Impaired cell-mediated
profile helper 2/humoral immunity [80] Dendritic cells (DCs) have a critical function as antigen-
phenotype presenting cells [41] but in HNSCC this function is also
B cells Poor generation of high- Impairment of impaired. The environment in which HNSCC develops,
affinity tumor antigen phagocytic effector
aerodigestive tract mucosa, is rich in immature myeloid
antibodies or cells renders antibody
antibodies produced recognition useless DCs and Langerhans cells [42]. Upon encountering
do not inherently harm [80] inflammatory signals (IL-1, TNF-a, etc.) or microbial
tumor cells products (i.e., TLR ligands) under physiological condi-
Complement Tumor cells express No complement damage tions, DCs migrate to secondary lymphoid organs and
cascade anti-complement to tumor cells [80]; mature into antigen-presenting cells capable of cross
factors complement proteins
may promote stimulating, priming, and promoting the expansion of
mutagenesis [81] effector T cells. Increased presence of DCs in tumor
Mast cells Secrete proteolytic Tumor migration and specimens is associated with longer disease-free survival
enzymes invasion [52] and decreased recurrence [43, 44], and fewer DCs are
found in high-grade tumors [45] and lymph nodes with
metastatic disease [46]. To avoid immune system recog-
relatively high presence of effector memory T cells [30], nition, tumors frequently prevent DC maturation and
further suggesting T-cell recognition of tumor. Albeit instead attract abnormal, immature DCs (iDCs) that actu-
stunted, effector T cells may still achieve some anti- ally promote T-cell dysfunction [5]. Immature DCs express
tumoral effect: effector T-cell infiltration in a tumor low levels of the necessary co-stimulatory CD80 and CD86

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molecules as well as MHC-II, which are necessary for
antigen presentation to CD4? T cells. These tolerogenic
DCs also induce production and proliferation of T regula-
tory cells, which are immunosuppressive immune cells
discussed below. Defects in DC maturation are also visible
systemically: HNSCC patients with advanced disease have
fourfold reduced levels of circulating myeloid-derived DCs
[47] as these cells accumulate in the lymph node sinuses
and tumor site in an immature form [48]. In addition to
iDCs, HNSCC tumors also simultaneously attract other
immature myeloid cells, including macrophages, granulo-
cytes, and myeloid-derived suppressor cells, which all
contribute to a pro-tumoral environment.
Tumor-associated macrophages
Tumor-associated macrophages (TAMs) are macrophages
known to support tumor progression via promotion of
humoral immunity and hindrance of cell-mediated immu-
nity [49]. TAMs are similar to M2 macrophages in that
they produce IL-10 and transforming growth factor b
(TGF-b) and secrete matrix remodeling proteases and
serine proteases that are associated with more advanced
tumor grade and metastasis [5052], higher microvessel
density in the tumor, and increased bioavailability of
VEGF [36]. TAMs can also directly secrete VEGF [36, 53,
54]. A paracrine loop has been suggested between TAMs
and tumor cells: tumor cells attract TAMs by secreting
monocyte chemotactic protein-1 (MCP-1) and TGF-b1,
and meanwhile, TAMs secrete VEGF, IL-8, TNF-a, and
IL-1, which stimulate tumors to secrete more VEGF and
IL-8 [1, 36, 55]. TAMs may contribute directly to extra-
capsular extension and lymph node metastasis as increased
TAM infiltration correlates with tumors with these features
[20, 56]. TAMs accumulate in the areas of fibrin deposition
in the tumor and peritumoral tissue, which suggests that
they aid in tumor matrix stabilization as well as angio-
genesis [36, 57].
Myeloid derived suppressor cells
MDSCs have emerged as a powerful mediator of the
immunosuppressive state. Recruited directly by tumors via
tumor-derived factors, MDSCs are CD34?CD33? imma-
ture myeloid cells that suppress CD8? T-cell proliferation
and promote tolerance through a variety of mechanisms,
including by producing TGF-b, removing L-arginine
(L-Arg) from the microenvironment, and nitrosylating
important T-cell motifs [58, 59]. L-Arg is essential for
correct CD3 complex expression in T lymphocytes [60].
MDSCs upregulate the enzyme L-arginase or the enzyme
nitric oxide synthase (NOS), both of which partake in
L-Arg metabolism [61, 62]. MDSCs S-nitrosylate cysteine
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residues of important signaling proteins in the IL-2
receptor pathway including JAK1, JAK3, STAT5, ERK,
and AKT, effectively rendering T cells unresponsive to IL-2
[58]. In addition, MDSCs can produce high quantities of
peroxynitrite which induces apoptosis [63] or anergy [64]
in activated T cells. NOS and peroxynitrate metabolites
have been found in HNSCC tumor beds [65, 66], and tumor
infiltration with CD34? MDSCs [59, 6769] is a negative
prognostic factor. MDSCs, like TAMs, also secrete matrix
remodeling proteases and series proteases, contributing to
tumor dissemination [5052].
Regulatory T cells
CD4?CD25?Foxp3? regulatory T cells (Tregs) are par-
ticularly important for the maintenance of peripheral tol-
erance and have been implicated in tumor-induced
immunosuppression by many studies. Tregs inhibit T-cell
activity via a number of mechanisms [70], including via the
production of TGF-b and IL-10 or the hydrolysis of
extracellular ATP to ADP or AMP by the ectoenzyme
CD39 [71]. Tregs also promote the generation of indole-
amine-2,3-dioxygenase (IDO) positive tolerogenic DCs by
expressing the cytotoxic T-lymphocyte antigen-4 (CTLA-4)
and engaging CD80 and CD86 on DCs [5, 70]. An increase
in CD4?CD25highFOXP3? has been associated with a poor
prognosis in many cancers [72]. Controversy does exist,
however, as FOXP3? cells infiltrating the tumor have been
proposed either as a positive [73, 74] or as a negative
prognostic factor in HNSCC [75, 76]. This controversy was
recently resolved by using computer-assisted image quan-
tification and by taking into consideration the subcellular
localization of FOXP3 [77]. Indeed, FOXP3? can be
expressed also by non-regulatory, activated effector T cells
[78]. While in regulatory T cells FOXP3 is found mainly in
the nucleus, in activated T cells FOXP3 seems to be
localized mostly in the cytoplasm [79]. By taking advan-
tage of these two conditions, a retrospective study in
patients with oral squamous cell carcinoma found that
while FOXP3 in the cytoplasm of tumor infiltrating CD4?
cells correlated with favorable prognosis, its nuclear
localization strongly predicted recurrence [77]. The ratio
between nuclear and cytoplasmic FOXP3 expression
within the tumor infiltrating CD4? T cells is proposed as a
powerful prognostic marker in HNSCC [77].
Tumor-derived factors in HNSCC
Head and neck squamous cell carcinoma cells effectively
hijack the immune system and control distribution of
supportive resources such as nutrients both locally and
distantly via release of tumor-derived factors (TDFs) [16].
Immunology & Microbiology in Miami (2013) 57:5269
These soluble factors are also able to condition distant sites
for eventual metastasis, leading to a tumor-driven macro-
environment beyond the local microenvironment. Numer-
ous TDFs have been identified for HNSCC, including
granulocytemacrophage colony-stimulating factor (GM-
CSF), prostaglandin E2 (PGE2), vascular endothelial
growth factor (VEGF), and various cytokines and chemo-
kines. A number of these factors are not completely pro-
tumor or anti-tumor, but rather play a dual role depending
on elements such as dose, concentration, and duration of
exposure.
Granulocyte macrophage-colony stimulating factor
Granulocyte macrophage-colony stimulating factor appears
to assume both anti-tumoral and pro-tumoral roles
depending on variations in amount, systemic concentration,
and duration of exposure. About 31 % of tested cancer lines
including HNSCC secrete GM-CSF [82, 83], and it is
associated with a negative prognosis [83]. At higher doses,
GM-CSF recruits MDSCs and promotes their differentiation
into effective pro-tumoral cells. Administration of tumor-
transduced GM-CSF, recombinant GM-CSF protein, or
high doses of GM-CSF vaccines leads to emergence of
MDSC cells [82, 84, 85], whereas administration of GM-
CSF neutralizing antibody in tumor conditioned media
inhibits MDSC differentiation [86]. On the other hand, GM-
CSF has been shown to elicit powerful immune responses
when combined with c-irradiated tumor cell vaccines in the
clinical setting and as a result has been used as an immune
adjuvant to augment antitumor immunity [87, 88]. GM-CSF
is also given to decrease the incidence of mucositis during
chemotherapy [89] as well as prevent potentially life-
threatening neutropenia. A bystander vaccine strategy was
used in which the antigen dose and steric hindrance were
maintained constant to test the doseeffect of GM-CSF, and
a threshold was identified above which significant immu-
nosuppression mediated by MDSC recruitment was induced
[85]. This may also explain why clinical trials demonstrated
a negative effect at doses between 100 and 500 lg, but not
at repeated low doses of 4080 lg for 15 days [90].
Prostaglandins
Head and neck squamous cell carcinoma tumors frequently
overexpress cyclooxygenase-2 (COX-2) [91, 92] as do
MDSCs, leading to the production of the eicosanoid pros-
taglandin E2 (PGE2), which correlates with arginase
overexpression, STAT3 and STAT1 phosphorylation, IL-10
and MIP-2 production, and resulting immunosuppression
[93]. PGE2 is able to activate the suppressive phenotype in
MDSCs and facilitate the differentiation of MDSCs from
their hematopoietic precursors [94]. PGE2 can also induce
57
Treg production [36]. Non-steroidal anti-inflammatory
drugs, which target COX-2, have been shown to exert
chemoprotective effects on HNSCC cancer development
[95].
Vascular endothelial growth factor
Released by most tumors, VEGF is well known for its role
in tumor angiogenesis [9698]. VEGF is also intimately
involved with MDSCs, with evidence suggesting that
VEGF administration leads to inhibition of DC develop-
ment and an increased number of MDSCs [99]. Meanwhile,
MDSCs secrete matrix metalloproteinase 9 (MMP-9),
which breaks down matrix proteins and allows for VEGF
permeation through the extracellular matrix [100]. In
HNSCC, VEGF-A expression correlated with microvessel
density, disease progression, a reduced number of mature
DCs, and an increased number of immature DCs and
MDSCs [101]. Elevated VEGF levels is a poor prognostic
factor and correlates with tumor stage and lymph node
status in HNSCC [102].
Cytokines
Cytokines are released not only by recruited immunosup-
pressive immune cells, but also by tumor cells that release
them to orchestrate a pro-tumoral effect [16]. HNSCC was
shown to produce IL-13 and IL-4, which promote the T
helper 2 response and an anti-inflammatory state [103,
104]. Many HNSCC tumors have IL-4 and IL-13 receptors
(IL4Ra and IL13Ra), which are constitutively over-
expressed, leading to excess arginase production and pro-
motion of neoplastic proliferation [105]. IL4Ra expression
on MDSCs and monocytes is required for their suppressive
phenotype [106, 107] and survival [107]. Most HNSCC
patients also have increased blood levels of IL-6 [108],
which is associated with a poor prognosis. IL-6 affects the
differentiation of myeloid lineages [109] by the activation
of STAT3 and may inhibit the maturation of DCs in par-
ticular [110]. Introducing IL-6 antibodies leads to restora-
tion of DC differentiation [111]. Indeed, bone marrow cells
treated with GM-CSF and either IL-6 or G-CSF were
shown to differentiate into suppressive MDSCs [112]. IL-6
also contributes to systemic symptoms seen in some
HNSCC patients including weight loss, night sweats, and
fevers [113].
Chemokines
Chemokines are important chemotactic molecules that can
not only bind to each other to form various signaling het-
erodimers [114, 115] but that can also bind to multiple
receptors. These receptors, in turn, can be activated by
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different chemokines, and this allows for chemokine
redundancy [116], robustness, integration [117], and syn-
ergy [118]. Consequently, individual chemokines have
been shown both to promote tumor immunity, such as by
recruiting T cells to the tumor site, and to promote tumor
survival, such as by recruiting MDSCs and TAMs [119].
CCL5 can complex with CXCL4 to influence monocyte
arrest; the same CCL5 can increase the antitumor effect of
adoptively transplanted T cells, but only if intratumoral
CD11c? cells are depleted [120]. CCL21 induces Th1
polarization and boosts DNA vaccine effects, and yet the
same chemokine is secreted by many human tumors [121]
and the expression of its receptor CCR7 correlates with
metastasis in HNSCC [122]. There are many more exam-
ples of the contradictory roles of chemokines, but research
is revealing more about the mechanisms behind each
beneficial or deleterious role. For example, CCL2 is known
to attract both cytotoxic T cells [123], MDSCs, and TAMs
[124127], yet T cells remain trapped in the stroma sur-
rounding cancer cells, whereas TAMs and MDSC can
freely travel within [128]. This occurs because reactive
nitrogen species produced by TAMs and neoplastic cells
induce nitration/nitrosylation of CCL2 that, once nitrosy-
lated, can no longer recruit cytotoxic T cells, but that can
still recruit myeloid cells to the tumor [129]. Understanding
chemokine interactions may be imperative for designing
immunotherapies capable of reaching the tumor and
exerting the desired tumoricidal or immunostimulatory
effect.
HPV1 HNSCC and the immune system
Whether a HNSCC tumor is HPV?or HPV- may have
important implications for its interaction with the immune
system. Notably, patients with HPV? tumors have a better
survival than those with HPV- disease: three-year survival
is 84 versus 57 %, and the median overall survival is
fourfold higher at 131 versus 20 months [130]. What
accounts for this difference? The answer may be that the
immune system is better able to assume a cytotoxic role. In
a preclinical study on immune-deficient mice, no differ-
ence in tumor growth was observed between transplanted
HPV? and HPV- tumors, while in immune-competent
mice, a significant delay in tumor progression was
observed and 2030 % of them cleared the tumor com-
pletely [131]. Tumor rejection was possible only when both
HPV-specific CD4? and CD8? T cells were present.
Indeed, HPV-infected cells are positive for the non-self,
virus-associated E7 and E6 antigens that can evoke a
powerful, generic, antiviral response. The differences
between HPV? and HPV- tumors may become more
important as we develop immunotherapies and immune
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prevention strategies. Indeed, with the distribution of the
HPV vaccine in children and young adults, evidence of a
decrease in HNSCC in the vaccinated cohorts is emerging
[132].
Immunotherapy for HNSCC
For HNSCC patients, a number of immunotherapeutic
strategies are being explored, and many treatments are
currently being tested in clinical trials. There are two main
categories of immunotherapeutic strategies: antigen non-
specific and antigen-specific. Antigen non-specific thera-
pies are designed to broadly enhance the immune response,
either by stimulating anti-tumoral mediators or by revers-
ing the immunosuppression put in place by the tumor.
Antigen-specific therapies are designed to cause a focused
immune response toward the tumor cells directly. Both
therapy types have yielded promising results, yet in most
cases there are limitations that need to be addressed.
Antigen non-specific therapies are frequently limited by
systemic toxicity, and antigen-specific therapies are often
limited by the powerful immunosuppressive environment
put forth by the tumor. Both therapy types may exhibit
variable efficacy depending on the specific mutations
present in a given tumor. Combination immunotherapies
are being explored in order to overcome these limitations.
Antigen non-specific therapies
Immune stimulation: cytokine treatment
As detailed above, tumors utilize cytokines to orchestrate
immunosuppression and create a pro-tumoral milieu.
Cytokine treatments attempt to shift the balance away from
the pro-tumoral, T helper-2 cytokine predominance and
toward anti-tumoral T helper-1/cytotoxic predominance
[80].
Interleukin-2
Interleukin-2 (IL-2) is one of the earliest cytokines
employed to treat HNSCC. Recombinant IL-2 given locally
by peritumoral, [133] intranodal, or intraarterial infusion
[134] to HNSCC patients leads to increases in intratumoral
NK cells and activity of tumor infiltrating lymphocytes
(TILs). These observation might be clinically significant
since the injection of IL-2 preoperatively around the cer-
vical lymph node chains prior to oral cavity or oropharynx
squamous cell carcinoma resection and radiotherapy led to
significant increases in disease-free and overall survival
[135]. These local treatments are generally well tolerated,
Immunology & Microbiology in Miami (2013) 57:5269
whereas systemic IL-2 is not. Systemic toxicities are sig-
nificant and include hypotension, capillary leak syndrome,
and oliguria [134] with only partial response rates near
18 % [136]. Following the principle of local delivery, the
fusion drug ALT-801, composed of IL-2 and a T-cell
receptor specific for the p53/HLA-A*0201 complex, has
been designed to target IL-2 to p53 positive tumors [133].
This treatment leads to higher efficacy and lower toxicity.
Interleukin-12
Interleukin-12 (IL-12) has been used with a similar goal of
immunostimulation in HNSCC patients. Intratumoral IL-12
injection led to increased B-cell tumor and lymph node
infiltration, B-cell activation, and a highly significant IgG
subclass switch measured in the plasma, indicating a switch
to Th1 phenotype [93]. IL-12 increased NK cells in the
tumor as well as led to a 128-fold increase in IFN-c mRNA
in lymph nodes [137, 138]. IL-12 is currently being
investigated in clinical trials [93] for efficacy.
Interferon-gamma
Systemic IFN-c therapy has been attempted in HNSCC
patients with 3 of 8 responding with minimal toxicity in
one study and 4 of 9 responding in a second study [139].
However, another trial failed to show any objective
response [140].
Interferon-alpha
IFN-a has been used in combination with cisplatin and 5-
fluorouracil in the treatment of advanced esophageal
squamous cell carcinoma with an overall response rate of
55 % but was associated with significant toxicity. When
combined with IL-12, IFN-a produced significant tumor
regression in 2 of 11 advanced HNSCC patients [141]. A
recent phase II trial investigated IFN-a combined with
isotretinoin and vitamin E in locally advanced HNSCC,
showing 5-year progression-free survival rate and overall
survival rate of 80 and 81.3 %, respectively [93].
Reversal of immunosuppression
Reversal of tumor-induced immunosuppression is the sec-
ond class of antigen non-specific strategies employed in
HNSCC. These strategies are designed to (1) reestablish a
micro- and macro-environment favorable for immunosur-
veillance; (2) deplete the suppressive populations that are
recruited by the tumor; and (3) block the molecular
mechanism of negative regulators of the adequate immune
response. Several of these therapies aim to inhibit aberrant
intracellular pathways involving VEGF, PGE2, GM-CSF,
59
IL-6, or other tumor-derived factors, while others target
specific immunosuppressive populations such as MDSCs
and T regulatory cells.
Tyrosine kinase inhibitors
Tyrosine kinases are commonly overexpressed and acti-
vated in many tumors including HNSCC [142]. Tumor-
derived factors promote also the aberrant activation of
these kinases in the hematopoietic system, leading to the
accumulation of, for example, MDSCs. Suntinib is a mol-
ecule that inhibits multiple tyrosine kinases (VEGFR-1,
VEGFR-2, VEGFR-3, PDGFR, c-kit, ret, STAT3, etc.),
and, as expected, shows potent effects against MDSCs
[143]. It has been shown to reverse MDSC accumulation
and induce tumor cell apoptosis in renal cell carcinoma.
[144]. Clinical trials using suntinib in HNSCC patients
demonstrated significant toxicities including lymphopenia,
neutropenia, and thrombocytopenia [145] and poor thera-
peutic efficacy [146, 147]. A number of other selective
kinase inhibitors are currently in development [142]. Some
tyrosine kinase inhibitor drugs are monoclonal antibodies
and will be discussed below.
1a,25-Dihydroxyvitamin D3
Vitamin D has been shown to induce the maturation of
MDSCs into immune-stimulatory DCs [148, 149] as well
as inhibit tumor production of VEGF and hypoxia factor 1a
(HIF-1a) [150], which are involved with the induction of
MDSCs by the tumor. Although it is not clear whether
vitamin D acts on MDSCs directly or indirectly, it has been
tested in HNSCC. Patients treated with vitamin D preop-
eratively had reduced amounts of MDSCs in the tumor
and increased amounts of mature DCs and activated T cells
(CD4? and CD8?) [151]. More importantly, the time
to recurrence was doubled in the patients who received
vitamin D. Nevertheless, more studies are needed to fur-
ther characterize the impact of vitamin D on HNSCC
survival.
Cox-2 inhibitors
COX-2 inhibitors reverse the PGE2 overproduction by
tumors and thus provide an opportunity to block MDSC
differentiation and activation [152]. Celecoxib, a specific
COX-2 inhibitor, when used in combination with radio-
therapy and Erlotinib, an EGFR receptor blocker, led to
37 % progression-free survival and 60 % locoregional
control at 1 year [153]. When combined with the EGFR
receptor blocker gefitinib, 22 % of unresectable or meta-
static HNSCC demonstrated a partial response [154].
While tolerated well during the study periods, celecoxib is
123
60
associated with dose-dependent cardiovascular morbidity
so its use in long-term treatment may be limited [155].
Phosphodiesterase inhibitors
Phosphodiesterase-5 (PDE5) can be targeted to reverse
MDSC suppression. Its inhibition, by controlling the
intracellular concentration of cGMP, is sufficient to inhibit
arginase 1, NOS2, and IL4a on MDSCs, thus reducing
their suppressive ability [156]. Moreover, it has been
shown that administration of the PDE5 inhibitors sildenafil
or tadalafil was sufficient to significantly reduce tumor
progression in murine models of breast and colon cancer
[156], while in a lymphoma model was able to restrain
MDSC-mediated expansion of tumor-specific Tregs [157].
More importantly, sildenafil was able to restore T-cell
proliferation in anti-CD3/anti-CD28-stimulated peripheral
blood mononuclear cells (PBMCs) from HNSCC patients
[157]. Two clinical trials (NCT00843635, NCT 00894413)
have recently closed to accrual utilizing daily tadalafil
administration prior to standard of care surgery or chemo-
radiation therapy in patients with HNSCC. While results of
these trials are not yet published, interim analysis of
NCT00843635 suggests that PDE5 blockade lowers MDSC
and Treg concentrations in the blood and tumor tissue and
expands the pool of tumor-specific CD8? cells (unpub-
lished data, updated September 2013).
Alkylating agents
Tregs are particularly sensitive to alkylating agents, and
thus, alkylating agents may play an immunotherapeutic
role. Indeed, cyclophosphamide or ifosphamide at low
doses can decrease Treg concentration in the blood [158,
159]. Interestingly, when cyclophosphamide was combined
with cisplatin and 13-cis retinoic acid, a response rate of
72 % for metastatic HNSCC was observed [160].
IRX-2
Combination therapies may be more effective than single
agents. A novel drug named IRX-2 was developed that
contains a mixture of the antitumoral cytokines IFN-c, IL-2,
IL-6, IL-8, IL-1b, G-CSF, GM-CSF, and TNF-alpha, as
well as agents that reverse immunosuppression, namely
indomethacin and cyclophosphamide [161]. Zinc is also
included as it is a necessary mineral for the development
of cellular immunity. Interestingly, zinc deficiency is
observed in 50 % of patients with HNSCC and correlates
with higher cancer stage [162]. Recently tested in a phase
II clinical trial, IRX-2 was given to Stage II-IVa HNSCC
patients for 21 days preoperatively; 83 % had stable
123
Immunology & Microbiology in Miami (2013) 57:5269
disease during treatment according to radiographic review,
and overall survival was 69 % at 36 months [162].
Additional antigen non-specific therapies are currently
being tested in other cancers; a recently published review
discusses anticipated HNSCC clinical trials based on these
additional therapies [36].
Antigen-specific therapies
Antigen-specific therapies are designed to enhance tumor-
specific responses generated by the natural immune system
and include antibody therapies, adoptive cell transfer, and
tumor vaccines.
Antibody therapies
A number of monoclonal antibodies have been developed
against a variety of tumor cell surface molecules. When the
antibody binds to the target molecule, it may inhibit the
tumor cell by directly blocking the signaling pathway ini-
tiated by the molecule, and/or by initiating cell-mediated
cytotoxicity resulting in tumor cell death. In cell culture,
tumor cell apoptosis only occurs after antibody adminis-
tration when lymphocytes are present [163, 164]. The
precise mechanism of tumor lysis is not well understood:
complement-dependent cytotoxicity can be seen with some
antibody therapies, but this mechanism of cell death should
occur rapidly, as should NK cell-mediated cell death, and
yet tumor shrinkage is noted over weeks, not hours; this is
more consistent with a T-lymphocyte-mediated lytic effect
[164]. Fc gamma R polymorphisms on antibodies should
variably influence any NK antibody-dependent cellular
cytotoxicity, yet this is not well elucidated [164, 165]. The
IgG subtype of the antibody appears to influence the effi-
cacy of the therapy; IgG1 and IgG3 subclasses are more
efficient than IgG2 and IgG4 at mediating lysis of target
cells [164, 166, 167]. Lysis of normal cells is also a risk as
normal cells also contain many of the surface antigen
molecules, yet antibody therapy does not typically result in
severe systemic toxicity [164].
The most widely studied antibodies for HNSCC are
those targeting the epidermal growth factor receptor
(EGFR), which is typically overexpressed on the majority
of HNSCC cells [16]. Cetuximab, an immunotherapy cur-
rently FDA approved for HNSCC, targets EGFR, which is
a receptor tyrosine kinase. A phase III trial in which ce-
tuximab was added to radiotherapy demonstrated an
increase in locoregional control from 14.9 to 24.4 months
(p = 0.005) with limited toxicity [168]. Overall 5-year
survival was also improved from 36.4 to 45.6 %, primarily
in patients that experienced at least a grade 2 acneiform
rash during treatment [169]. Efficacy of cetuximab and
Immunology & Microbiology in Miami (2013) 57:5269
other EGFR antibody therapies is limited by HNSCC
resistance through upregulation of other receptor tyrosine
kinases such as HER2, HER3, and MET, altered EGFR
function after nuclear translocation, and altered expression
of downstream effectors of EGFR signaling [142]. Com-
bination therapy may be necessary to increase efficacy. A
number of additional antibody therapies for HNSCC are
also being studied, including ones that target HER2/neu,
VEGF, CD45, CTLA-4, PDL-1, or carcinoembryonic
antigen (CEA) [93]. Various monoclonal antibody thera-
pies for HNSCC have been recently reviewed [36, 164,
170, 171].
Overall, antibody-based immunotherapy for HNSCC
has the greatest clinical efficacy and the most widespread
use in clinical practice today as compared to other immu-
notherapies. However, further investigation is needed in
order to increase antibody effectiveness, perhaps by com-
bining with agents that reverse local immunosuppression.
Conjugated antibodies, in which the antibody is conjugated
with a radioactive substance, drug, or toxin, are an alter-
native strategy for antibody therapy designed to take
advantage of antibody specificity as a means of targeted
delivery of a non-immunotherapeutic agent. One conju-
gated antibody tested in a HNSCC phase I clinical trial was
186
Re-labeled humanized bivatuzumab, which demon-
strated that the drug was well tolerated and led to delivery
of a median of 12.4 Gy to the tumor cells [172]. Studies
evaluating the use of other labeled or loaded antibodies to
treat various cancer cell types are ongoing [173].
Adoptive cell transfer
Adoptive cell transfer involves harvesting and priming a
patients own tumor antigen-specific effector cells before
re-introducing them to the patient. In one such trial, 17
patients with HNSCC were injected in the thigh with
irradiated autologous tumor cells admixed with GM-CSF
followed by 3 additional injections of GM-CSF at the site
[174]. The following week, the inguinal lymph nodes
draining the injection site were resected, and the lympho-
cytes harvested from these nodes were activated with
staphylococcal enterotoxin A and expanded in IL-2
in vitro. The CD3-enriched cells were then infused back
into the patients peripherally. Three patients had disease
stabilization where progression had been evident prior to
the treatment. Another trial involved 4 patients in which
harvested peripheral blood mononuclear cells (PBMCs)
were collected by leukophoresis and then incubated ex vivo
with catumaxomab, a monoclonal antibody that binds
CD3? T cells with one arm and epithelial cell adhesion
molecule (EpCAM) with the other [175]. Catumaxomab-
loaded PBMCs were shown to release IFN gamma and
gramzyme B when coincubated with EpCAM? cells. After
61
opsonization and cytokine washout, the cells were rein-
troduced into the patients. One patient showed stable dis-
ease for 6 months and another went into complete
remission during the follow-up period of 27 months. A
recent study made use of bimodal ex vivo expansion to
expand harvested tumor infiltrating lymphocytes using
anti-CD3 antibody, feeder cells, and high-dose IL-2. Just
17 days were required to create up to 3,500-fold expansion
of the T cells, most of which were T-effector memory cells
[31]. This method may be used in the future for clinical
trials in HNSCC patients. Adoptive cell transfer techniques
have also been studied for NK T cells, and one study
demonstrated tumor regression in 5 out of 10 locally
recurrent, operable HNSCC patients [176].
As with other immunotherapies, adoptive cell transfer
has its limitations that still need to be overcome. Not only
is the technique cumbersome and technically challenging,
but also many tumor-specific lymphocytes that pre-exist in
the patient are anergic to in vitro re-stimulation [177]. A
new strategy involving gene modification of T lympho-
cytes may be a solution [135, 178]; PBMCs from patients
are retrovirally transduced with a T-cell receptor (TCR)
specific for the tumor, and additional genes that protect the
lymphocytes from the tumor suppressive mechanisms can
also be added [179]. In a study with melanoma patients,
PBMCs were transfected with high-affinity T-cell receptors
specific for p53HLA-A2 complex and were shown to be
able to recognize different human tumor cells lines
expressing p53 [180]. As many HNSCC tumors express
p53 [181, 182], this may become a potential therapy for
HNSCC patients.
Anti-tumor vaccines
Dendritic cell-based vaccines
Dendritic cell counts are generally reduced in HNSCC
patients, but patient monocytes can be used to generate
autologous DCs in vitro, or allogeneic DC lines can be
manipulated. These DCs loaded with TAAs such as p53
[183], tumor RNA [184, 185], or tumor DNA [36] are
being used as vaccines in patients. These TAA-specific
DCs are able to produce IFN-c in vitro [184, 186]. Stage
I-IVa HNSCC patients with no active disease were vacci-
nated with autologous DC pulsed with p53 and a tetanus-
derived helper peptide. A phase I clinical trial [187]
demonstrated the safety of this vaccine and an increase in
p53-specific T cells in 11 of 16 patients. Frequencies and
absolute numbers of Tregs were significantly decreased
after vaccination. More importantly, disease-free survival
at 24 months appeared to be favorable as compared to
historical unvaccinated HNSCC patients.
123
62
Peptide-based vaccines
Peptide-based vaccines, also known as Trojan vaccines, Additional clinical trials with OncoVEX are ongoing.
utilize a penetrin peptide sequence derived from HIV-TAT,
which allows the entire peptide to translocate through the
cell membrane and penetrate directly into the endoplasmic
reticulum and the Golgi apparatus [188]. Once there, they
can form peptideHLA complexes without the need of
proteasome processing and TAP transportation. This ther-
apeutic modality has been attempted in a pilot study with
HNSCC patients. MAGE 3 and HPV-16 peptides fused to
the penetrin peptide were used in 4 consecutive immuni-
zations with GM-CSF and Montanide ISA 51 as adjuvant.
Most patients demonstrated systemic immune response
against the Trojan and HLA-II-restricted peptides [189].
Analysis of the tumor specimen from one patient after
treatment revealed significant infiltration of MAGE-spe-
cific CD4? and CD8? T cells as well as large areas of
apoptotic tumor cells. Phase II clinical trials using MAGE-A
and HPV-16 antigens are currently ongoing [36].
Whole tumor vaccines
Whole tumor vaccines attempt to target the whole reper-
toire of tumor antigens so as to minimize the chance that
further immunoediting and subsequent tumor resistance.
One technique involves re-injecting autologous irradiated
tumor cells into patients along with GM-CSF and then
harvesting the sentinel node lymphocytes that are theoret-
ically sensitized to multiple TAAs for subsequent adoptive
cell transfer [174], as already described above. Another
strategy involves using oncolytic viruses with genes
encoding immune-stimulatory cytokines such as GM-CSF
[190]. The rationale for use of these viruses is that they
selectively replicate in a tumor leading to lytic tumor cell
death and also lead to release of tumor antigens along with
stimulating cytokines, inducing a tumor-specific immune
response that protects the host from local and distant
recurrence. A phase I trial of OncoVEXGM-CSF, which
consists of a herpes simplex virus expressing GM-CSF,
was conducted on stage III/IV HNSCC patients. Pre-
liminary data demonstrated that 6 of 8 patients had a
complete pathologic response with only mild toxicity
[191]. Another study was conducted in which the virus was
injected intratumorally in stage III/IVA/IVB HNSCC
patients in conjunction with neoadjuvant chemoradiother-
apy [192]. All patients underwent neck dissection 6
10 weeks later. 82.3 % of the patients showed tumor
response by Response Evaluation Criteria in Solid Tumors,
and pathologic complete remission was confirmed in 93 %
of the patients at neck dissection. HSV was detected in
injected and adjacent uninjected tumors at levels higher
than the input dose, indicating viral replication. No patient
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Immunology & Microbiology in Miami (2013) 57:5269
developed locoregional recurrence, and disease-specific
survival was 82.4 % at median follow-up of 29 months.
Therapeutic HPV vaccines in HNSCC
Therapeutic HPV vaccines are being developed that target
E6 and E7, which are constitutively expressed in HPV-
infected cells [193]. These vaccines include the use of
HPV-E6 peptides, live attenuated listeria monocytogenes
bacteria carrying E7 fusion protein, Trojan peptides, vac-
cinia based vaccines, naked DNA vaccines, and DC-based
vaccines [194]. The vaccine utilizing listeria is interesting
in that it takes advantage of the capacity of listeria to infect
antigen-presenting cells and promote DC antigen cross-
presentation; subsequently, effector T cells are activated
while the innate immune system is simultaneously stimu-
lated by the bacteria [195]. Preclinical data demonstrate
that this technique induces the regression of established
tumors by reducing the suppressive activity of Tregs and
MDSCs at the tumor site, by promoting the chemotaxis and
maturation of DCs, and by generating memory effector T
cells [196]. In a phase I trial of refractory cervical cancer
patients receiving the listeria-based vaccine, 1-year sur-
vival increased to 53 % from the historical 5 %, with a
significant reduction in tumor size in 33 % [197]. Various
clinical trials with HPV vaccines are ongoing [198].
Conclusion
Recent advances in our understanding of the complex
interactions between HNSCC and the immune system have
led to a number of innovative immunotherapeutic strate-
gies. While most of these strategies are still investigational,
their existence represents both a hope for improved
HNSCC survival in the near future and an opportunity to
shape the future of immunologic cancer research. It is
increasingly apparent that efforts to generate an effective
anti-tumor immune response must be coupled to strategies
that work to abrogate the strong immunosuppressive net-
work orchestrated by the tumor. As more is discovered
about the role of immune system in carcinogenesis, the
opportunity for earlier intervention may also become pos-
sible. HNSCC remains a debilitating and deadly disease,
yet through the enthusiastic study of its interaction with the
immune system, the promise of immunotherapy is stronger
than ever.
Acknowledgments This work was supported by the Flight Atten-
dant Medical Research Institute (FAMRI)s young investigator
award, by the Bankhead Coley Cancer Research Program Grant
2BF0650904.
Immunology & Microbiology in Miami (2013) 57:5269
Conflict of interest The authors declare that they have no conflict
of interest.
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