Aryssa Lagman; BMLS-3D Causative Agents of Human Cancer

FINALS LECTURE 2: TUMOR IMMUNOLOGY

Introduction Causes Examples Effects
 Oncology—B ranch of medicine devoted
1. Chemicals Nicotine in cigarettes Lung, esophageal, urinary
to the study of diagnosis, prevention and bladder cancers
treatment of tumor Aflatoxin (A. flavus) Liver cancer
 Tumor—proliferation of cells  mass; not Alcohol Liver cancer
Aspartame (diet soda) Proliferation of cancer
an inflammatory response (swelling)
Carbon in BBQs Colon cancer
 Benign: harmless; noncancerous 2. Radiation Ultraviolet light Skin cancer
 Malignant: virulent; deadly
o Progressive growth & invasiveness 3. Viruses Epstein-Barr Virus Hodgkin's lymphoma
o Metastatic
HIV Karposi sarcoma
Hepatitis B/Hepatitis C Hepatocellular carcinoma
Benign Tumors Human Papilloma Virus Cervical cancer
 Etymology 4. Bacteria Helicobacter pylori Gastric carcinoma
 From Latin benignus, meaning "well"
 Often named by adding the suffix -oma to the cell type Malignant Transformation: Retrovirus (RNA virus)
 Etiology  In some cases, retrovirus can induce growth change in cells  due
 Exact cause is often unknown; slow growth; don't spread to presence of oncogenes (cancer producing genes) on the virus
 Can arise from:  Process/step:
o Glands—adenoma 1. Initiation  changes the genome of the cell
o Fat cells—lipoma 2. Promotion  stimulation of cell division
o Bone—osteoma 3. Progression  development of tumor
o Cartilage—chondroma
o Fibrous tissue—fibroma Example: Rous Sarcoma Virus (v-Src)
 Genes:
Malignant Tumors  Normal genes: proto-oncogenes or cellular oncogenes
 Viral gene: retroviral oncogenes
 Etymology
 Insertion of virus to a normal cell  Malignant Transformation
 From Latin malignare, meaning malicious or "likely to rebel"  Result: Change in growth of cell (rapid proliferation)
 Abnormal cell growth with the potential to invade or spread  Why?
 Etiology  Conversion of cellular proto-oncogene to cancer promoting oncogene
 There are over 100 different known cancers affecting humans  due to MUTATION
 Can arise from:  Cellular oncogenes normally codes for growth controlling proteins
o Squamous epithelium - squamous cell carcinoma
o Glandular epithelium - adenocarcinoma Oncogenes & Effect on Cell Growth
1. Stimulators of cell division
Classification of Tumor (Basis: embryonic origin) a. Encodes growth factor
 Carcinomas  developed from endodermal or ectodermal tissues
Regulates cell
b. CHON for signaling division
(e.g. skin & glands) pathways
 Constitute majority of malignant tumors (cancer of breast, c. Transcription factors
lung, & colon) 2. Tumor Suppressor Genes
 Sarcomas  develop from bone and cartilage  Inhibitors of cell
 Leukemias  malignant cells of hematopoietic lineage that division/anti-oncogenes
Regulates cell
proliferate as individual cells 3. Regulators of Apoptosis division

 Lymphomas  arise from malignant hematopoietic cells but grow  Ration of Bcl2 to BAX
as a solid tumor protein determines
whether cell undergoes
Mechanism of Metastasis programmed cell death

Tumor Antigens
 Tumor expresses antigens on their surface
 IR
 Tumor Ags (cellular peptides) 
presented by MHC  stimulates Ag
specific T cell proliferation
 Kinds: tumor markers
 Variant forms of normal protein
 From dev stages or lineage
 Fd at higher than normal concentration
 Unique to tumors: TSTAs

Tumor Specific Transplantation antigens (TSTAs):

MECHANISM OF MALIGNANT TRANSFORMATION  Not found on normal somatic cells
 Expressed by the tumor cells
Malignant Transformation: Exposures  Identification of TSTAs on naturally occurring tumors is difficult
 Cells exposed to:  Reason:
 Certain microorganism  Immune response generally eliminates TSTAs at levels great
 Radiation enough to be antigenic
 DNA-altering chemicals
 Produce altered growth Tumor-Associated Transplantation Antigens (TATAs)
properties  induces tumors  Not unique to tumor cells but rather their expression on tumor
development cells is altered
 Tumor antigen is present in excessive amounts
o Ex. Human Breast Cancer: high levels of growth factor receptor
Neu
 Expressed on a cell type where it would not normally exist
o Ex. Oncofetal antigens (alpha-fetoprotein)  fd in fetal liver and
serum of pt with liver carcinoma
 IMMUNE SURVEILLANCE Antibody Modulation of Tumor Antigens
Theory:  Presence of Antibodies against tumor
 Cancer cells when present antigens  downregulates the
within the body are normally expression if tumor specific antigens
eliminated before they  Antigenic Modulation:
multiply & becomes clinically
 Ags disappear fir a time & reappears
detectable.
 Tumors arise only when they when Ab is eliminated
are able to escape immune  Cells that do not express the Ag 
surveillance. no longer a target of Adaptive IR
 Immune surveillance: The
immune system is on patrol
for abnormal cells, often
halting malignant cell growth
before tumors arise. Only
those malignant cells that
escape immune detection become clinical tumors.
Modulation of MHC I Expression
 Tumor cell expressed reduced level
2 Ways of Immune Surveillance of MHC I
1. Innate  NK cell responses may be enhanced
 The mechanism to prevent the spread are not specific to a  While, CTL mediated responses
particular tumor antigen against are decreased
2. Adaptive
 Specific antigen-dependent immune response

INNATE IMMUNE SURVEILLANCE

NK CELLS
 KAR: Stressed molecules
 KIR: MHC class I
Note:
 When a KAR is engaged, the kill
Mechanisms of Tumor Immune System Evasion
signal is activated
 If the KIR is engaged, do not kill
signal is received by the NK cell
 ALSO, Fc receptor on NK cells
can bind to Ab present on
tumor cells leading to antibody
dependent cellular cytotoxicity

CYTOKINES
 Macrophages secrete cytokines 2. Ag-CD3
with antitumor activity 3. MHC I-CD8 1. B7-CD28
1. TNF (alpha & beta)  stimulates 1. The tumor will not express antigen
necrosis of tumor cells 2. The tumor will not express MHC Class I
 TNF alpha  inhibits
3. The tumor will not express B7
angiogenesis
2. Interferons (alpha, beta, gamma)
 increase MHC expression on Peripheral Tolerance: T cell
tumor cell  increase Clonal Anergy/T cell anergy
susceptibility to CTLs (Cytotoxic T  Lack of reaction by the body's defense mechanism to foreign
Lymphocyte) substances
 IFN gamma  directly inhibit T cell activation APC T cell
proliferation of tumor cells 1st signal MHC + Ag CD3
2nd signal B7 (or CD80/86) CD28

4. The tumor will express Fas ligand

ADAPTIVE IMMUNE T lymphocytes
SURVEILLANCE recognizing Fas
1. ANTIBODIES  Generated
ligand will be
against certain tumor specific tricked into
antigens, present on the surface
killing itself so
of malignant cells that instead of
2. CTLs  Kill tumor cells by direct
tumor cell
contact being
3. DTH  Involves Th1 recruiting eliminated, the
& activating macrophages, T cells are the
which attack & kill tumor cells ones that die

5. The tumor will shed its own antigens

MECHANISMS OF IMMUNE ENVASION:
A. Antibody Enhancement of Tumor Growth
B. Antibody Modulation of Tumor Antigens
C. Modulation of MHC I expression

Antibody Enhancement of Tumor Growth

The antitumor antibodies may bind to the antigens on the tumor
cells, masking the antigens and blocking the ability of CTL cells to
bind and kill tumor cell
6. The tumor cell with loose its antigen variants  Vaccination, either to prevent development or inhibit recurrence
of tumor needs to be further explored

Tumor Markers
A tumor is a biomarker found in blood, urine, or body tissues that
can be elevated by the presence of one or more types of cancer

This tumor can still engulf the immune complex thereby hiding it away from
the complement system and thus prevent cell lysis

7. The tumor will secrete a glycocalyx coat (barrier)

CD8
Tc
????
CD8
Tc

8. The tumor will imitate Th3 cell function

IL-10 CD8
Tc

SUPRESSED

Tumor Immunosurveillance vs Tumor Editing

 Tumor Immunosurveillance - the immune system identifies cancerous

and/or precancerous cells and eliminates them before they can cause harm
 Tumor editing - undergoes additional mutation thus escaping the immune
system forming malignant cancers

Viral vs Chemical Induced Tumors

CANCER IMMUNOTHERAPY
 Is designed to enhancement
the natural immune
responses that the body
mounts against malignant
cells
1. Cytokine therapy
2. Monoclonal Antibodies
3. Cancer vaccines
 limited effect

Cancer Vaccines
 Identification of a virus
responsible for malignant transformation
 Human Papillomavirus on cervical cancer
 Immunization HPV  Prevents infection by virus  Prevents
development of cervical cancer