CANCER IMMUNOLOGY

TABLE OF CONTENT

INTRODUCTION 01 02 TUMOR ANTIGEN

An interdisciplinary branch of biology concerned An antigenic substance to trigger
with the role of the immune system and  in the the immune response in the host
progression and development of cancer 

IMMUNE RESPONSE TO TUMOR 03 04 CANCER IMMUNOTHERAPY

A Tool towards Immunotherapy An approach to treat cancer with the
Natural defense mechanism
01
INTRODUCTION
 CANCER IMMUNOLOGY

• Cancer is characterized by genetic and epigenetic instability leading to multiple unique and sometimes
common mutations and “ectopic “ overexpression of many genes normally not expressed in the tissue of
origin.

• These alterations provide antigens that the adaptive immune system can recognize to distinguish the
cancer cell from normal cells.

• Thus the immune system of a patient with cancer has the potential to selectively recognize his or her
cancer

• A major focus of recent student in cancer immunology is the immune microenvironment. Multiple cells
and molecular interactions in the tumor microenvironment inhibit antitumor immune responses.

• These cells include regulatory T cells and myeloid-derived suppressor cells,which accumulate in tumors.
Both cell types suppress cytotoxic T-cell responses that threaten tumors with destruction.
 1.Lymphoma

TUMORS OF IMMUNE SYSTEM 2.Leukemia

3.Myeloma
Leukemias:
Leukemia can develop as single cell and are detected by increase in cell number in blood and lymph. It
can be developed in myeloid or lymphoid lineages.
Historically, it is classified on the basis of progression of disease. They are:
• Acute leukemia
• Chronic leukemia

ACUTE LEUKEMIA CHRONIC LEUKEMIA

01 Progress rapidly Progress slowly

02 Results in several ill, needs immediate Can be asymptomatic and treatment can be
treatment. delayed.
03 Common in younger age groups Common in older age groups

04 Prognosis is predictable Prognosis is unpredictable

05 Includes Acute Lymphocytic Leukemia(ALL) Includes Chronic Lymphocytic Leukemia (CLL)

and Acute Myelogenic Leukemia (AML) and Chronic Myelogenic Leukemia (CML)
06 Normal level of inflammatory cytokines Increased level of pro inflammatory cytokines
 Lymphoma:

• Lymphoma proliferate as solid tumors within a Lymphoma tissue such as bone marrow, Lymph nodes
and thymus.

• The main types of Lymphoma are

1. Hodgkin’s Lymphoma
2. Non-Hodgkins Lymphoma

Myeloma:
• A cancer of plasma cells.

• In this condition, the cancerous plasma cells accumulate in the bone marrow and crowd out healthy
blood cells. Rather than produce helpful antibodies,the cancer cells produce abnormal proteins that
can cause complications.
 Enhancement of Tumors

By AntiTumor Antibodies
• The immunization of the tumor itself sometimes did not protect against tumor growth, but actually
enhance the growth of tumor.

• Here the antitumor antibodies itself act as as a blocking factor.

By Antigenic Modulation
• Certain tumor specific antigens are observed to disappear from the surface of tumor cells in the
presence of serum antibody and then to reappear after the antibody is no longer present. Thus
phenomenon is called Antigenic modulation.
 Enhancement of Tumor

By Poor Expression of Class-I MHC Molecules

• CD8+ CTLs recognize antigens only associated with class-I MHC molecules.

• Any changes in the expression of class-I MHC molecules will decrease the CTL mediated immune
response.

• Many tumors show decrease level of class-I MHC molecules.

• The decrease in its expression is often accompanied by progressive tumor growth and so the
absence of MHC molecule on Tumor cell is generally indication of poor prognosis.
 Enhancement of Tumor

Requirement of Stimulatory and Costimulatory signals

• Activation signal: It is triggered by recognition of a peptide MHC molecules complex by the T-cell
receptor.

• Co-stimulatory signal: It is triggered by the interaction of B7 on antigen presenting cells with CD28 on
the T-cells.

• Both these signals are needed to induce IL-2 production and proliferation of T-cells.
02 A Stand up to Cancer
TUMOR ANTIGEN
 TUMOR SPECIFIC ANTIGENS

• TSA‘s are the resultant from mutations in the Tumor cell that generate the altered
proteins and thereby,new antigens.

• Cytosolic processing of these proteins then gives rise to novel peptides that are
presented with class 1MHC molecules, including a cell mediated response by
Tumor specific CTL’s.

• These antigens can be quite diverse and are only identified by their ability to
induce T-cell mediated rejection.

• Many of these antigens are not cell membrane proteins; rather,they are short
peptides derived from cytosolic proteins that have been processed and presented
together with the class 1 MHC molecules.

• In some cases, the presence of virus-specific Tumor antigens is an indicator of

neoplastic transformation.
 TUMOR ASSOCIATED ANTIGENS

• TAA‘s represents normal cellular proteins typically expressed only during

specific developmental stages,such as in the fetus, or at extremely low
levels in normal conditions,but which are upregualted in Tumor cells.

• Those mutated fetal or embryonic genes,called oncofetal tumor

antigens.

• Two oncofetal antigens are:

1. Alpha fetoprotein (AFP)
2. Carcino embryonic antigen (CEA)

• The category of TAA’s also includes the products of some oncogens,

such as several growth factors and growth factor receptors.
 Difference between TSA & TAA

Tumor Specific Antigen Tumor Associated Antigen

• Expressed by Tumor cells • Self antigens expressed by Tumor cells

• Not present in normal cells • Present in a subset of normal host cells

• Arise mostly from oncogenic driver mutation that • Arise mostly from genetic amplification
generate novel peptide sequences, i.e neoantigens • Or post translational modifications

• Can also be generated by oncoviruses.

• Tendency for expression that is higher
• Example: • And potential for tumor cells
Alphafetoprotein (AFP) expression in germ Example :
cell tumors and hepatocellular carcinoma. •
Melanoma associated antigen (MAGE) expressed in the
testis along with malignant melanoma
Immune
response to
Tumor

03 Tool to Immunotherapy…..
HUMORAL IMMUNITY:

1. Humoral antibodies do not appear to confer significant protection against tumor growth.

2. Humoral antibodies that react with tumor cells invitro have been detected in the Sera of patients with
various tumors such as Burkitts lymphoma, melanoma, osteosarcoma,neuroblastoma and breast
carcinoma.

3. Some population of humoral antibodies, called enhancing antibodies (blocking antibodies),may actually
favor rather than inhibut Tumor growth.

CELLULAR IMMUNITY:
1. T cell is the primary cell responsible for direct recognition and killing of tumor cells.

2. T cells carry out immunologic surveillance,proliferate and destroy newly transformed tumor
cells after recognizing TAAs

3. In contrast,suppressor T cells inhibit the immune response against tumors.

CYTOTOXIC T LYMPHOCYTES:
1. CTLs recognize antigens on target cells and lose these cells.

2. These antigens may be cell surface proteins Or may be intracellular proteins (eg, TAAs) that are
expressed on the surface in combination with class I MHC molecules.

3. Tumor specific CTLs have been found in Sarcomas, Carcinomas, Melanomas.

NATURAL KILLER (NK) CELLS:

1. NK cells are effector cells with tumoricidal activity. Their tumoricidal activity is termed natural because
it is not induced by a specific antigen.

2. Evidence suggests that I MHC molecules on the surface of normal cells inhibit NK cells and prevent
lysis.

3. Thus, the decreased level of class I molecule expression characteristic of many Tumor cells may allow
activation of NK cells and subsequent tumor lysis.
MACROPHAGES :
1. Macrophages can kill specific tumor cells when activated by a combination of factors, including
lymphocytes (soluble factors produced by T cells) and interferon

2. They are less effective than T-cell mediated cytotoxic mechanisms. Under certain
circumstances,Macrophages may present TAAs to T cells and stimulate tumor specific immune
response.

DENDRITIC CELLS:
1. Dendritic cells are dedicated antigens presenting cells Present in barrier tissues (such as skin, lymph
nodes). They play a central role in initiation of tumor specific immune response.

2. These cells take up tumor-associated proteins,process them, and present TAAs to T cells to
stimulate the CTL response against tumor. Several classes of Dendritic cells can mediate tumor
promotion or suppression.
LYMPHOKINES :
1. Lymphokines produced by immune cells stimulate growth or induce activities of other immune cells.

2. Such Lymphokines include interleukin-2 (IL2) and interferons. IL-12 is produced by dendritic cells
and specifically induces CTLs, thereby enhancing antitumor immune responses.

MYELOID-DERIVED SUPPRESSOR CELLS:

1. Myeloid-derived suppressor cells consist of immature myeloid cells and their precursors. These cells
increase in number in cancer, inflammation and infection. The cells have potent immune suppressive
activity.

2. These cells accumulate in large numbers in cancers and predict poor clinical outcomes in various
types of cancer.
 Elimination of Tumor Cells
Over the past decade there has been notable progress in the concept of cancer immunosurveilance and
immunoediting based on.,
1. Protection against development of spontaneous and chemically induced tumors in animal systems.
2. Identification of targets for immune recognition of human cancer.

CANCER IMMUNOSURVEILLANCE :
An important host protection process that inhibits carcinogenesis and maintains regular cellular homeostasis.

IMMUNOEDITING :
It is a process by which a person Is protected from cancer growth and the development of tumor
immunogenicity by their immune system.
This process consists of three phases:
1. Elimination
2. Equilibrium
3. Escape
• Elimination phase corresponds to the concept cancer immunosurveillance, whereby nascent tumor
cells are successfully recognized and eliminated by the immune system, thus returning the tissues to
their normal state of function.

• Tumor cells that elude the immunosurveillance phase will progress to the immune editing phase,called
the equilibrium phase of advanced oncogenesis, where tumor expansion and metastasis are minimal
and usually occur without symptoms.

• In the Equilibrium phase, the immune system may eventually eliminate all tumor cells leading to an
outcome similar to the elimination phase.

• In a second scenario,the constant interaction of the immune system with tumors over a long period of
time may actually “edit” or sculpt the phenotype of the developing tumor,resulting in the
immunoselection of a tumor that has been shaped into a less-immunogenic state.

• Tumors that are no longer susceptible to immune attack then progress into the process,termed
“Escape phase”. The emergence of clinical symptoms of cancer generally correlates with the escape
stage.

• Tumor subverts the immune system,either directly through its non immunogenic phenotype or indirectly
through a variety of immunosuppressive mechanisms.
 Cancer
Immunotherapy

04
 1. Manipulation of co-stimulatory signals can enhance immunity

● It has been demonstrated that Tumor immunity can be

enhanced by providing the co-stimulatory signal necessary for
activation of CTL precursors (CTL-Ps).

● When melanoma cells are transfected with the gene that

encodes the B7 ligand, then the CTL-Ps differentiate into
effector CTLs.

● Normal mice were first immunized with irradiated, B7

transfected melanoma cells and then challenged with unaltered
malignant melanoma cells.
 2. Enhancement of APC activity can modulate Tumor immunity

● Mouse dendritic cells cultured in GM-CSF & incubated

with tumor fragments,then reinfused into the mice, have
been shown to activate both Helper-T cells and CTLs
specific for the tumor antigens.

● When the mice were subsequently challenged with live

Tumor cells, they displayed Tumor immunity.
 3. Adjuvant mediated immunity boosters

● A number of adjuvants including the attenuated strains of Mycobacterium bodies called Bacillus
Calmette Guerin (BCG) & Corynebacterium parvuum have been used to booster immunity.

● These adjuvants activate macrophages, increasing their expression of various cytokines,

class II MHC molecules & the B7 co-stimulatory molecule.

● These activated macrophages are better activators of Th cells,

resulting in generalized increases in both humoral & cell mediated responses.
 4. Cytokine therapy can augment immune responses to tumors

● The isolation and cloning of the various cytokine genes has facilitated their large scale production.

● A variety of experimental & clinical approaches have been developed to use recombinant
cytokines, either singly or in combination to augment the immune response against cancer.

● Among the cytokines that have been evaluated in cancer immunotherapy are : IFN α, β, γ
IL1, IL2, IL4,IL5,IL12, GM-CSF &TNF.
 5. Interferons (IFN)

● Daily injections of recombinant IFN α have been shown to induce partial or complete tumor
regression in some patients. In some patients with hematology malignancies such as
leukemias,lymphomas & myelomas and with solid Tumors such as melanoma, Kaposi’s
sarcoma, renal cancer and breast cancer.

● All three types of interferons have been shown to increase class I MHC expression on Tumor
cells.

● IFN γ has also been shown to increase class II MHC expression on macrophages.

● IFN γ, directly or indirectly increases the activity of TC cells, macrophages & NK cells, all of
which play a role in the immune response to tumors cells.
 6. Tumor Necrosis Factors (TNF)

● In the presence of TNFα and TNFβ, a tumor

undergoes visible hemorrhagic necrosis and
regression.

● TNFα has shown also been shown to inhibit

tumor induced vascularization by damaging
vascular endothelial cells in the vicinity of a
tumor, thereby decreasing the flow of blood
and oxygen that is necessary for progressive
tumor growth.
 7. Invitro activated LAK & TIL cells

● Animals studies have shown that lymphocytes can be activated against tumor antigens invitro by
culturing them with X-irradiated tumor cells in the presence of IL2.

● These activated lymphocytes mediate more effective tumor destruction than untreated
lymphocytes when they are reinjected into the original tumor bearing animal

● Tumors contain lymphocytes that have infiltrated the tumor and presumably are taking part in an
antitumor response.

● These population of lymphocytes can be expanded invitro with IL2.

● These activated Tumor-Infiltrating Lymphocytes are called TILs and have increased antitumor
activity.
 THANK YOU

References:
• Immunology by Kuby
• Roitts’s essential Immunology
• Cancer immunology @ sciencedirect.com
• www.cancer.gov
• Cellular and molecular immunolgy by Abul Abbas