IMMUNITY

TO
TUMOR
introduction
Cancer is a major health problem worldwide and one of the
most important causes of morbidity and mortality in
children and adults.
Cancer arise from the uncontrolled proliferation and
spread of clones of transformed cells.
The concept of immune surveillance of cancer, which was
proposed by Macfarlane Burnet in the 1950s, states that a
physiologic function of the immune system is to recognize
and destroy clones of transformed cells before they grow
into tumors and to kill tumors after they are formed.
01
GENERAL FEATURES
OF TUMOR IMMUNITY
Tumors stimulate specific adaptive immune responses that can prevent or limit the
growth and spread of the cancers. ( Many tumors are surrounded by mononuclear cell
infiltrates composed of T-lymphocytes, naturalkiller [NK] cells, and macrophages, and
that activated lymphocytes and macrophages are present in lymph nodes draining the
sites of tumor growth)
 The first experiment demonstration that tumors can induce protective immune
responses came from studies of transplanted tumors performed in the 1950s
(Methylcholanthrene, MCA)
 Immune response frequently fail to prevent the growth of tumors:

~ First, tumor cells are derived from host cells (weakly immunogenic)
~ Second, the rapid growth and spread of tumors
~ Third, many tumors have specialized mechanisms for evading host

The immune system can be activated by external stimuli to

effectively kill tumor cells and eradicate tumors (immunotherapy)
02
TUMOR
ANTIGENS
The earliest classification of tumor antigens was based on their patterns of expression
~ tumor-specific antigens: Antigens that are expressed on tumor cells but not on normal cells
~ tumor-associated antigens: Tumor antigens that are also expressed on normal cells

The modern classification of tumor antigens relies on the molecular structure and source of the antigens

To purify and characterize these antigens were based on producing monoclonal antibodies specific for
tumor antigens

A more recently developed approach for identification of tumor antigens specifically is called serologic
analysis of recombinant cDNA expression (SEREX)

Tumor antigens (peptides) that are recognized by T cells are likely to be the major inducers of tumor
immunity and the most promising candidates for tumor vaccines
 NEOANTIGENS: ANTIGENS ENCODED BY MUTATED GENES

The protein neoantigens of tumors are mostly the products of randomly

mutated genes ("passenger mutations") reflecting the genetic instability of
cancer cells or, less commonly, products of mutated oncogenes or tumor
suppressor genes that are involved in oncogenesis ("driver mutations").

Tumor antigens are produced by oncogenic mutants of normal cellular genes

Often, these genes are produced by point mutations, deletions, chromosomal translocations,
or viral gene insertions affecting cellular proto oncogenes or tumor suppressor genes
Peptides derived from them do not induce self-tolerance (circulating CD4+ and CD8+T cells
that can respond to them)
Mutated oncogenes such as Ras and Bcr-Abl proteins and mutated tumor supressor genes
such as p53
 ANTIGENS OF ONCOGENIC VIRUSES

The products of oncogenic viruses function as tumor antigens and elicit specific T cells responses
that may serve to eradicate virus-induced tumors.

Epstein-Barr virus (EBV), B cell lymphomas and nasopharyngeal carcinoma,

Human papillomavirus (HPV), cervical carcinoma
Papovaviruses, including polyomavirus and simian virus 40 (SV40), and adenoviruses induce
malignant tumors
Because the viral peptides are foreign antigens, DNA virus-induced tumors are among the most
immunogenic tumors known
RNA tumor viruses (retroviruses) are important causes of tumors in animals
Human retrovirus that is known to cause tumors is human T cell lymphotropic virus 1 (HTLV-1),
adult T cell leukemia/lymphoma (ATL), a malignant tumor of CD4+ T cells
Patients with ATL are often profoundly immunosuppressed, probably because the virus infects
CD4+ T cells
 OVEREXPRESSED CELLULAR PROTEINS

Some tumor antigens are the product of the genes that are silenced in normal cells and
derepressed in tumor cells, or are proteins made by normal cells but produced in
excessive amounts by tumors.
Normal cellular proteins that are abnormally expressed in tumor cells and elicit
immune responses
One such antigen is tyrosinase, an enzyme involved in melanin biosynthesis that is
expressed only in normal melanocytes and melanomas
Tyrosinase-specific T or tyrosinase vaccines
Cancer/testis antigens are proteins expressed in gametes and trophoblasts, and in
many types of cancers, but not in normal somatic tissues (MAGE proteins expressed
in other tumors in addition to melanomas, including carcinomas of the bladder,
breast, skin, lung, and prostate, and some sarcomas)
 OTHER ANTIGENS OF TUMORS
*Oncofetal Antigens*

Oncofetal antigens are proteins that are expressed at high levels in

cancer cells and in normal developing fetal but not adult tissues

These antigens are increased in tissues and in the circulation in various

inflammatory conditions and are found in small quantities even in normal
tissues

Carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP)

 CARCINOEMBRYONIC ANTIGENS (CEA):

CEA (CD66) is a highly glycosylated integral membrane protein, of the immunoglobulin (Ig)
superfamily, an intercellular adhesion molecule that functions to promote the binding of tumor
cells

High CEA expression is normally restricted to cells in the gut, pancreas, and liver during the first
two trimesters of gestation, and low expression is seen in normal adult colonic mucosa and the
lactating breast

CEA expression is increased in many carcinomas of the colon, pancreas, stomach, and breast

The level of serum CEA is used to monitor the persistence or recurrence of the tumors after
treatment
 ALPHA FETOPROTEIN (AFP):

Alpha-Fetoprotein (AFP) is a circulating glycoprotein normally synthesized and

secreted in fetal life by the yolk sac and liver

Elevated in patients with hepatocellular carcinoma, germ cell tumors, and,

occasionally, gastric and pancreatic cancers

useful indicator of advanced liver or germ cell tumors or of recurrence

 *Altered Glycolipid and Glycoprotein Antigens*

Most human and experimental tumors express higher than normal levels or
abnormal forms of surface glycoproteins and glycolipids, which may be diagnostic
markers and targets for therapy

These altered molecules include gangliosides, blood group antigens, and mucins

Melanomas are the gangliosides GM2, GD2, and GD3

Clinical trials immunotherapy of anti-GM2, anti-GD3 and anti-GM2 antibodies in

melanoma

Mucins including CA-125 and CA-19-9, expressed on ovarian carcinomas, and MUC-
1, expressed on breast carcinomas
03
IMMUNE RESPONSE
TO TUMORS
 ADAPTIVE IMMUNE RESPONSE TO TUMORS
*T-Lymphocytes*
The principal mechanism of tumor immunity is killing of tumor cells by CD8+ CTLs
that associate with class I MHC molecules

CD8+T cell responses specific for tumor antigens may require cross presentation of
the tumor antigens by professional APCs, such as dendritic cells in class II MHC

APCS express class II MHC molecules that may present internalized tumor antigens
and activate CD4+ helper T cells

Helper T cells specific for tumor antigens may secrete cytokines, such as TNF and
IFN-y, that can increase tumor cell class MHC expression and sensitivity to lysis by
CTLs
 *Antibodies*
Against various tumor antigens, as EBV-encoded antigens expressed on
the surface of the lymphoma cells

Antibodies may kill tumor cells by activating complement or ADCC

 INNATE IMMUNE RESPONSE TO TUMORS
*NK Cells*
NK cells kill many types of tumor cells, especially cells that reduced
class I MHC expression

ADCC with FCYRIII

The tumoricidal capacity of NKC is increased by cytokines, including

interferons and interleukins (IL-2 and IL-12)

lymphokine- activated killer (LAK) cells as adoptive immunotherapy,

IL-2
 *Macrophages*
In vitro, activated macrophages can kill many tumor cells more efficiently than they
can kill normal cells

Possible mechanisms include direct recognition of some surface antigens of tumor

cells and activation of macrophages by IFN-y produced by tumor specific T cells

Activated macrophages also produce the cytokine tumor necrosis factor (TNF)
04
EVASION OF IMMUNE
RESPONSES BY TUMORS
 MECHANISMS BY WHICH
TUMORS ESCAPE IMMUNE
DEFENCES:
Immune Checkpoints: Inhibitions of immune Responses
Tumor-associated macrophages (M2 phenotype) may promote tumor growth and
invasiveness by altering the tissue microenvironment and by suppressing T cell
responses

Regulatory T cells may suppress T cell responses to tumors

Myeloid-derived suppressor cells (MDSCs) are immature myeloid precursors that

are recruited from the bone marrow and accumulate in lymphoid tissues, blood, or
tumors of tumor-bearing animals and cancer patients and suppress anti tumor
innate and T cell responses
 Loss of Tumor Antigen Expression
Reduced immunogenicity, a process that has been called "tumor editing"

Tumor antigens may induce specific immunological tolerance

Regulatory T cells may suppress T cell responses to tumors

Tumors lose expression of antigens that elicit immune responses

Tumors may fail to induce CTLs because most tumor cells do not express
costimulators or class II MHC molecules

The products of tumor cells may suppress anti-tumor immune responses, as TGF-ẞ
or Some tumors express Fas ligand (FasL), glycocalyx molecules
05
IMMUNOTHERAPY
FOR TUMORS
Treating cancer has held great promise for oncologists and

immunologists specific for tumor antigens and will not

injure most normal cells

Immunotherapy for tumors aims active immunity or to

administer tumor specific antibodies or T cells (passive

immunity)
 CHECKPOINT BLOCKADE: BLOCKING
T-CELLS INHIBITORY PATHWAYS
Blockade of T-cell inhibitory molecules has emerged as one of the most
promising methods for effectively enhancing patients immune
responses to their tumors. This approach is based on the idea that
tumor cells exploit various normal pathways of immune regulation or
tolerance to evade the host immune response, as discussed earlier.
Because these inhibitory mechanisms establish checkpoints in immune
responses, the approach of stimulating immune responses by a drug
that inhibits the inhibitors is called checkpoint blockade.

Inhibitory receptor for B7, called CTLA-4

 VACCINATION WITH TUMOR
ANTIGENS
Immunization with killed tumor cells or tumor antigens

Identification of peptides recognized by tumor-specific CTLs

And the cloning of genes with injection of plasmids containing cDNAs encoding
tumor antigens (DNA vaccines)

Tumor antigens, such as the MAGE, tyrosinase, and gp100 antigens on melanomas
and mutated Ras and p53 proteins are potentially useful immunogens

Virally induced tumors can be blocked by preventive vaccination with viral

antigens or attenuated live viruses
 ADOPTIVE CELLULAR THERAPY
WITH ANTITUMOR T-CELL
Adoptive cellular immunotherapy is the transfer of cultured immune cells
that have antitumor reactivity into a tumor-bearing host.

Chimiric Antigen Receptor T-cell Therapy

Adoptive therapy using T-cells expressing chimeric antigen receptors (CARs) has
proven successful in some hematologic malignancies, and this approach is in trails
for other tumors.
 PASSIVE IMMUNOTHERAPY WITH
ANTIBODIES

Passive immunotherapy is comprised of antibodies and other immune

system component that are made outside the body and administered
to the patients to provide immunity against the disease

It do not stimulate a patient immune system to actively respond to a

disease in the vaccines does.
 OTHER APPROACHES FOR STIMULATING
ANTITUMOR IMMUNTY
*Cytokine Therapy*
Cancer pateints can be treated with cytokines that stimulate the
proliferation and differentiation of T-lymphocytes and NK-cells.
 *Nonspecific Inflammatory Stimuli*

Immune responses to tumors may be stimulated by the local administration of

inflammatory substances or by systemic treatment with agents that function as
polyclonal activators of lymphocytes.

*Graft-Versus-Leukemia Effect*

In leukemia patients, administration of T-cells and NK-cells together with

hematopoietic stem cells from an allogeneic donor can contribute to eradication
of the tumor
Role of immune system in promoting of tumors
Chronic inflammation (H. Pylori in gasteric ca. and chronic hepatitis B and C virus
in hepatocellular ca.)

Chronic activation of innate immune cells, notably macrophages, is characterized

by angiogenesis and tissue remodeling, both of which favor tumor formation

Innate immune cells can also contribute by generating free radicals that cause
DNA damage and lead to mutations in tumor suppressor genes and oncogenes

Mast cells, neutrophils, and macrophages, secrete soluble factors that promote
cell-cycle progression and survival of tumor cells
THANK YOU!