1. SUBMITTED TO:
Dr.S.VISWANATHAN
HEAD OF THE DEPARTMENT
SRI PARAMAKALYANI COLLEGE
Reaccredited with A+ grade with CGPA 0f 3.39 in the III cycle of NAAC
Affiliated to Manonmaniam Sundaranar University, Tirunelveli
ALWARKURICHI-627412
Post graduate & Research Centre-Department of Microbiology
(government aided)
ACADEMIC YEAR 2022-2024
2ND SEM CORE:IMMUNOLOGY
UNIT-4 TUMOR IMMUNOLOGY
2. Tumor immunology has been defined as part of immunology that deals
with the antigens on tumor cells and the immuneresponse to them. As a
consequence of their loss of differentiation,tumor cells may express
developmental antigens that are usually seen only in the prenatal
period.
Examples of these antigens are alpha-fetoprotein and carcinoembryonic
antigen. Tumors or neoplasia is said to develop when the balance between
cell death and renewal is disturbed in a way that numerous clones of a
single cell group are produced in an uncontrolled fashion.
3. ■ A tumor that is not capable of indefinite growth and doesnot invade the healthy
surrounding tissue extensivel yis benign.
■ A tumor that continues to grow and becomes progressively invasive is
malignant; the term cancer refers specifically to a malignant tumor.
■ In addition to uncontrolled growth, malignant tumors exhibit metastasis; in this
process, small clusters of cancerous cells dislodge from a tumor,
invade the blood or lymphatic vessels, and are carried to other tissues,
where theycontinue to proliferate. In this way a primary tumor at one site
can give rise to a secondary tumor at another site.
4.
5. 1. Once cells become malignant, they stop functioning normally
and add to the burden on the body by competing with the normal
cells for space and nutrition.
2. The more “undifferentiated” a cell is, the lesser its functionality
and more its malignant nature.
3. They undergo rapid and uncontrolled division.
4. They lose their homing instinct and start invading the basement
membrane and enter the vasculature to spread to dissimilar
tissues, leading to metastasis and spread of cancer.
6. It has been postulated that the immune system is responsible in part for
the protection of the body against the development of malignancies. At
the same time, the prevalence of numerous cancers in immunocompetent
individuals indicates that immune system has only a partial role in
protecting against malignancies and also that it is not very efficient at it.
7. TUMOR ANTIGENS
Tumor cells also express unique molecules that can be classified into two
groups:
1. Tumor-specific antigens
2. Tumor-associated transplantation antigens
8. ◗ Tumor-specific antigens
The tumor-specific antigens (TSAs), also called tumor-specific
transplantation antigens, are unique to tumors. They are not found on
other cells of the body. They are usually the products of mutated genes
seen in the cancer cells. Cytosolic processing of the abnormal proteins
yields peptides that are unique and when presented by the appropriate
MHC class I molecules elicit a cell-mediated immune response.
9. Various physical and chemical carcinogens cause malignancies by inducing
mutation in key genes involved in modulating cell growth. Ras proto-
oncogene products including the p21 Ras proteins and other related gene
products are an example of TSAs. Ras proteins bind guanine nucleotides
(GTP and GDP) and possess intrinsic GTPase activity. The mutations
associated with Ras genes in malignant cells appear to cause a single amino
acid substitutions at specific positions (12, 13, or 61), which results in
increased enzymatic activity of the gene product. As a consequence, the
cells acquire transforming capacity. Moreover, these products are also
recognized as foreign antigens by the cellular immune response.
10.
11. Another mode through which the tumor cells may express unique and
novel antigens “is by” integration with proviral genomes. These virus-
induced tumors usually have their genome integrated with proviral
genome, hence the proteins encoded and expressed are sometimes novel
and recognized by the cellular immune response. Viruses that have been
implicated in tumorigenesis include Epstein–Barr virus (EBV), hepatitis B
virus (HBV), hepatitis C virus (HCV), etc.
12. ◗ Tumor-associated transplantation antigens
Tumor-associated transplantation antigens (TATAs) are the other class of
tumor antigens. These antigens are expressed by (a) tumor cells and also
by (b) normal cells at low levels or only during the process of
differentiation. The expression of these antigens is considerably
derepressed or enhanced after the process of malignant transformation.
TATAs can be of the following types:
1. Tumor-associated carbohydrate antigens: They represent abnormal
form of mucin-associated antigen detected in breast and pancreatic
cancers.
13. 2. Differential antigens: These include CD10 and prostate specific antigens
(PSA). The latter is used as a diagnostic indicator in prostatic cancer.
3. Oncofetal antigens: These antigens are found in embryonic and malignant
cells but are absent in normal adult cells. Alphafetoprotein and
carcinoembryonic antigens are examples of this antigen, which are found in
hepatomas and colonic cancers, respectively. Silent tumor-associated
genes are not expressed in normal cells but are actively transcribed in
tumor cells. Tissuespecific genes or differentiation genes are present in the
surface of normal cells or may be shed to the circulation, but the levels of
expression are usually very low in normal cells. This finds practical
application in the diagnosis of malignancies as illustrated by the assay of
PSA for the diagnosis of carcinoma of prostate.
14. PSA: It is a kallikrein-like serine protease produced exclusively by the
epithelial cells in the prostate gland. The antigen is detectable at relatively
high levels in seminal plasma and at very low levels in the serum of healthy
men. The assay of serum PSA levels is a very useful marker of prostate
carcinoma, perhaps the most meaningful serum marker for neoplasia. In
healthy men, the levels of PSA vary between 0.65 +/- 0.66 ng/mL at ages
21–30 and 1.15+/- 0.68 ng/mL at ages 61–70. Significantly elevated levels
are demonstrated in 63–86% of patients with prostatic carcinoma,
depending on the stage. In essence, antigens of tumors that are capable of
eliciting an immune response may be one of the following nature:
15. ■ First, these antigens are uniquely expressed by tumor cells alone. Also, there are
the products of genes that have been mutated during the process of
transformation, leading to the expression of abnormal products.
■ Second, certain antigens expressed by tumors are present only when normal cells
are undergoing the process of differentiation and these are also readily
recognized by the immune system.
■ Finally, the antigens that are overexpressed by the tumorcells elicit a good immune
response.
16.
17.
18. IMMUNE REACTIONS AGAINST TUMORS
Tumor antigens are capable of eliciting a comprehensive immune response
involving both the cellular and humoral immune responses.
◗ Cellular immune responses
T lymphocytes play an important role in tumor immunity. They act both as
cytotoxic effector cells and as central modulating cells. Through these effector
cells, they control the specific cellmediated antitumor immune responses and
upregulate nonspecific killing mechanisms. The activation of T lymphocytes by
tumor cell products as a consequence of antigen recognition may result in the
secretion of nonspecific immunoregulatory factors.
19. ■ These factors are capable of “upregulating” the tumorkilling function of
mononuclear phagocytes, NK cells, and granulocytes.
■ These factors also enhance the ability of NK cells and monocytes to participate
in ADCC against tumor cells
■ Macrophages also play an important role in tumor response. Clustering of
macrophages around tumor cells is associated with tumor regression
and seen in the case of numerous cancers.
20. ◗ Humoral immune responses
B lymphocytes produce tumor-specific antibodies, which may induce
complement-dependent cytotoxicity of tumor cells or may mediate
ADCC. ADCC can be mediated by a variety of cells expressing Fc?
receptors (NK cells, monocytes or macrophages, and granulocytes) by
recognizing and destroying IgG-coated tumor cells.
21. IMMUNOSURVEILLANCE
The emergence of cancer cells within the body may not be a rare or
unusual event at all. Of the trillions of normal cells found in the body,
several hundred per day may be undergoing malignant degeneration in
response to the cancer-promoting stimuli. The immune system may
possibly play a significant role in halting the growth of these cells and
preventing the development of overt malignancy.
22. The concept of immune surveillance was initially put forward by Ehrlich,
and later on modified by Thomas and Burnet. Ehrlich first suggested that
though cancer cells frequently arise in the body, they are recognized as
foreign and eliminated.
Later, Burnet postulated the immunosurveillance theory. He suggested
that the immune system routinely patrols the cells of the body and upon
recognition of a cell or a group of cells that has become cancerous
attempts to destroy them, thus preventing the growth of some tumors.
23. IMMUNO THERAPY OF CANCER
Immunotherapy of cancer can be considered as the
following
two broad groups:
1. Antigen-nonspecific treatment
2. Antigen-specific treatment
24. ◗ Antigen-nonspecific treatment
This includes treatment with various nonspecific immune modulators:
■ Bacillus Calmette–Guérin (BCG) vaccine has been shown to possess
antitumor activity. The vaccine when injected directly into certain solid
tumors may cause regression of tumor. Antitumor effect of tumor is
believed to be due to activation of macrophages and NK cells. The BCG
therapy has been reported to be beneficial in treatment of bladder
cancer, malignant melanomas, stage I lung cancer, and certain
leukemias.
25. ■ Corynebacterium parvum also possesses antitumor activities. Its
antitumor effect is due to its ability to stimulate macrophages and B cells.
It shows a synergistic effect when used in conjunction with
cyclophosphamide. It is found to be useful in treatment of metastatic
breast cancer and various types of lung cancer.
26. ■ Other nonspecific immune modulators include (i) dinitrochlorobenzene (DNCB),
evaluated in squamous and basal carcinoma, (ii) levamisole for stimulating
cell mediated immunity and macrophage function, (iii) interferon to
stimulate NK cell function, (iv) cytokine IL-2 to stimulate killing of cancer
cells by cytotoxic T cells, (v) NK cells, and macrophages, thymic hormones
to restore T cell function, and (vi) tuftsin to stimulate phagocytic cells.
27. ◗ Antigen-specific treatment
Antigen-specific treatment includes (a) vaccination with tumor
antigen, (b) treatment with transfer factor, (c) treatment with immune
RNA, (d) treatment with monoclonal antibodies raised against tumor-
associated antigens (TAAs) given alone or in conjunction with
cytotoxic drug, and (e) modification of tumor antigenicity by
treatment with neuraminidase.
