Download Cancer Immunology

Objectives
Introduction
 Ags expressed by cancer cells
 Nature of immune response
 How cancer evades immune
system
 Immunotherapy

Cancer
Introduction
Uncontrolled growth produces a tumor or
neoplasm.
 A tumor that grows indefinitely and often
spreads (metastasis) is called malignant-also called cancer.
 A tumor that is not capable of indefinite
growth----benign.
 Malignant---kills host.
 Benign---does not kill host.

Molecular Basis of Cancer
Mutations
Radiation
Chemical (Carcinogen)
Virus
Uncontrolled
cell growth
Proto-oncogenes
Tumor-suppressor
genes
Types of cancers based on etiologic agent

Chemically-induced tumors
 Each
tumor induced by a carcinogen (e.g. benzopyrene)
injected at various sites expresses a unique Ag.
 Thus difficult to develop vaccine.

Virus-induced tumors
 Tumors
induced by same virus express same tumor Ag.
 Induce a strong immune response.
Human Papilloma Virus (HPV) induced cervical cancer

UV-induced tumors
 UV
radiation--->melanomas
 Highly tumorigenic
Evidence for the role of immune system in
tumor rejection
Infiltration of tumors by lymphocytes and
macrophages
 Regression of metastases after removal of
primary tumor
 Regression after chemotherapy
 Lymphocyte proliferation in draining lymph
nodes
 Higher incidence of cancer after
immunosuppression/immunodeficiency
(AIDS, neonates, aged, transplant patients)

Antigens expressed on tumor cells
Major Histocompatability
Complex antigens
TSTA Tumor-specific
transplantation Ag
TATA Tumor-associated
transplantation Ag
TSTA: unique to a tumor
Play an important role in tumor rejection.
TATA: shared by normal and tumor cells
Tumor-associated developmental Ag (TADA)
Tumor-associated viral Ag (TAVA)
Tumor-Associated Developmental Ags
Found on cancer cells and on fetal cells.
 Do not trigger anti-tumor immunity.
 Used in diagnosis.

 Alpha-fetoprotein(AFP)
Cancers of liver
 Carcinoembryonic Ag (CEA)
colorectal
cancer
Other Tumor associated antigens
Differentiation Ags: B cells produce surface Ig.
B cell tumors have sIg
 Overexpression of Ag on tumors compared to
normal cells e.g. In breast cancer, HER2/neu
 Ags expressed on male germ cells and melanoma
e.g. MAGE-1

Tumor Antigen
Antitumor Effector Mechanisms
Immune surveillance : Recognize and destroy clones of transformed cells before they
grow into tumors and to kill tumors after they are formed.
Cytotoxic T-cell
Humoral
Mechanisms
NK cell
Macrophage
Tumor Immunity
Tumor and activated T cells
Two major pathways for TCL: Fas-mediated and perforrin-mediated
How does a tumor escape
immune surveillance?


Generation of Regulatory cells (CD4+CD25+ FoxP3+ T
cells) or Myeloid-derived suppressor cells(Gr-1+
CD11b+)
Secrete immunosuppressive molecules Ex:
Transforming growth factor beta (TGF-b), interleukin10 (IL-10), etc.
T regs
CTL
Tumor
MDSC
IL-10, etc

Failure to process and present tumor Ag.
tumor Ag
tumor
Macrophage
B cell
MHC Class II
T helper (Th) cell
MHC Class I
tumor
tumor
Cytotoxic T
lymphocyte (CTL)
Tumors
may fail to express costimulatory
molecules involved in T cell activation.
tumor
Class I MHC
B7
CD28
tumor Ag
CTL
Tumors escape the action of CTL by not expressing B7
which provides 2nd signal involved in T cell activation

Downregulation of MHC expression on
tumor cell (CTL resistant but NK
sensitive)
NK cell
Tumor
cell
Tumor escape mechanisms:
Fas
FasL
Tumor
FasL
Tumor
CTL
Fas
CTL
When tumor cells express Fas Ligand,
they can kill Fas+ T cells, thereby escaping
immune destruction.
Traditional approaches to treat cancer
Surgery
Localized tumors
Radiation
Chemotherapy
Metastastic tumors
Affects proliferating cells
(bone marrow, etc.)
Radiation/Drug-resistant tumors
Novel Mode: Immunotherapy
Immunotherapy

Active Immunization: The host actively elicits
an immune response.
 Specific
 Vaccination with viral Ags: e.g.
 Hepatitis B virus
 Human Papilloma virus (HPV) Gardasil

Nonspecific:

BCG (Bacillus Calmette-Guerin)
Mycobacteria - melanoma, bladder
carcinoma
Normal
Mf
Activated
Mf
Tumor
Tumor
lysis

Passive Immunization: Preformed Abs or immune
cells transferred
 Specific: Ab Therapy
 Abs against growth factor receptor e.g. IL-2R in
HTLV-1 induced Adult T cell leukemia
IL-2R
Anti-IL-2R
IL-2
 Abs
specific for oncogene product e.g. Abs
against HER2/neu (Herceptin or trastuzumab)
 Anti-tumor
Abs coupled to toxin,
radioisotopes, drugs or enzymes:
Tumor
Ricin
Immunotoxins:
Ricin A/diphtheria/Pseudomonas toxin
coupled to Abs. e.g. antiCD20-Pseudomonas
toxin in B cell leukemia
Internalized toxin inhibits protein synthesis.
Cytokine Therapy
Inject cytokines.
1. Interleukin -2 (IL-2) high dose - Alone or
with cells
Melanoma and renal cell carcinoma
Activates NK and CTL
Toxic - fever, edema, shock
2. Tumor necrosis factor (TNF-a) -Carcinoma
SUMMARY
Tumors should express TSTA.
 Th cells and CTL are important in tumor
rejection.
 NK cells and macrophages also play an
important role.
 Tumors evade immune system in a
number of ways.
 Immunotherapy is promising.
