The document discusses immunosurveillance, which is the concept that the immune system prevents tumour development by detecting and eliminating abnormal cells. It provides a history of the theory and describes the mechanisms by which the immune system responds to tumour antigens through cellular and humoral responses. However, tumours can evade the immune system through mechanisms like antigen loss or suppression of immune cells. While the immune system plays a role in controlling cancer, its theory is imperfect as tumours still develop, requiring updated concepts like cancer immunoediting.
3. DEFINITION
â– IMMUNOSURVEILLANCE IS A CONCEPT THAT
ENVISAGES PREVENTION OF THE DEVELOPMENT OF
MOST TUMOURS THROUGH EARLY DETECTION OF
ABNORMAL CELLS BY THE HOST’S IMMUNE SYSTEM.
5. â– The immune surveillance theory was first conceptualized
in the early 1900s by Paul Ehrlich. He suggested that
cancer cells frequently arise in the body but are
recognized as foreign and eliminated by the immune
system .
■He stated that: “in the enormously complicated course of
foetal and post-foetal development, aberrant cells become
unusually common. Fortunately, in the majority of people,
they remain completely latent thanks to the organism’s
positive mechanisms.”
â– This hypothesis was not proven experimentally at the time
due to the inadequacy of experimental tools and
knowledge.
6. â– Some 50 years later, Lewis Thomas suggested that the cell-
mediated branch of the immune system had evolved to patrol
the body and eliminate cancer cells. According to these
concepts, tumours arise only if cancer cells are able to escape
immune surveillance, either by reducing their expression of
tumour antigens or by an impairment in the immune response
to these cells.
7. â– Sir Frank Mac Farlane Burnet hypothesized
that tumour cell neo-antigens induce an
immunological reaction against cancer and
subsequently formulated the immune
surveillance theory.
■He wrote that: “It is by no means
inconceivable that small accumulation of
tumour cells may develop and because of
their possession of new antigenic potentialities
provoke an effective immunological reaction
with regression of the tumour and no clinical
hint of its existence.”
8. â– However, the theory of
immunosurveillance was
imperfect, because, tumours do
develop in the presence of a
functioning immune system.
â– Therefore, in 2002, the updated
concept of CANCER
IMMUNOEDITING was developed
by Dr. Robert D. Schreiber.
11. The immune system is a remarkably versatile defense
system that has evolved to protect animals from
invading pathogenic microorganisms and cancer.
IMMUNE
RESPONSE
RECOGNITION
RESPONSE
13. â– HUMORAL IMMUNE
RESPONSE
â– The effectors of the
humoral branch are
secreted antibodies,
highly specific molecules
that can bind and
neutralize antigens on
the surface of cells and
in the extracellular
spaces.
â– The primary domain of
antibody protection lies
outside the cell.
â– CELL MEDIATED
IMMUNE RESPONSE
â– The principal role of
cell-mediated immunity
is to detect and
eliminate cells that
harbour intracellular
pathogens.
â– Cell-mediated immunity
also can recognize and
eliminate cells, such as
tumour cells, that have
undergone genetic
modifications so that
they express antigens
not typical of normal
cells.
16. Cytotoxic T lymphocytes.
â– Cytotoxic T lymphocytes, or CTLs, are generated by immune activation of T
cytotoxic (TC) cells.
â– These effector cells have lytic capability and are critical in the recognition and
elimination of altered self-cells (e.g., virus-infected cells and tumour cells) and in
graft-rejection reactions.
â– In general, CTLs are CD8+ and are therefore class I MHC restricted, although in
rare instances CD4+ class II–restricted T cells have been shown to function as
CTLs.
â– Since virtually all nucleated cells in the body express class I MHC molecules,
CTLs can recognize and eliminate almost any altered body cell.
22. Natural Killer Cells
â– Natural Killer Cells make up 5- 10% of the circulating lymphocyte population.
â– These cells are involved in immune defences against viruses and tumours.
â– Because NK cells produce a number of immunologically important cytokines, they
play important roles in immune regulation and influence both innate and adaptive
immunity.
â– In particular, IFN-Y production by NK cells can affect the participation of
macrophages in innate immunity by activation of the phagocytic and microbicidal
activities.
â– NK cells are the first line of defense against virus infection, controlling viral
replication during the time required for activation, proliferation, and
differentiation of CTL-P cells into functional CTLs at about day 7.
23. • Natural killer cells appear to kill tumour cells and virus-
infected cells by processes similar to those employed by CTLs.
Despite these similarities, NK cells differ from CTLs in several
significant ways.
â– First, NK cells do not express antigen- specific T-cell
receptors
â– Recognition of target cells by NK cells is not MHC
restricted.
â– NK-cell response generates no immunologic memory.
25. An activation receptor (AR) on
NK cells interacts with its
ligand on normal and
altered self-cells.
However, engagement of
inhibitory NK cell
receptors by class I MHC
molecules delivers an
inhibitory signal that
counteracts the acti-
vation signal.
Expression of class I
molecules on normal cells
thus prevents their
destruction by NK cells.
Class I expression is often
decreased on altered self-
cells, the killing signal
predominates, leading to
their destruction.
26. ANTIBODY DEPENDANT CELL
MEDIATED CYTOTOXICITY
â– Antibodies are the antigen- binding proteins secreted by plasma cells and are present on the B-
cell membrane.
â– A number of cells that have cytotoxic potential express membrane receptors for the Fc region of
the antibody molecule.
â– When antibody is specifically bound to a target cell, these receptor-bearing cells can bind to the
antibody Fc region, and thus to the target cells, and subsequently cause lysis of the target cell.
â– Although these cytotoxic cells are nonspecific for antigen, the specificity of the antibody directs
them to specific target cells.
â– This type of cytotoxicity is referred to as antibody-dependent cell-mediated cytotoxicity (ADCC).
29. TUMOUR SPECIFIC
TRANSPLANTATION ANTIGENS
(TSTAs)
they are unique to
tumour cells and do
not occur on normal
cells
they may result from
mutations in tumour
cells that generate
altered cellular proteins.
cytosolic processing of
these proteins would give
rise to novel peptides that
are presented with class I
MHC molecules, inducing
a cell-mediated response
by tumour-specific CTLs
TUMOUR ASSOCIATED
TRANSPLANTATION ANTIGENS(TATAs)
not unique to
tumour cells
may be proteins that are
expressed on normal cells
during foetal development
when the immune system is
immature and unable to
respond but that normally
are not expressed in the
adult.
Reactivation of the embryonic
genes that encode these
proteins in tumour cells
results in their expression on
the fully differentiated tumour
cells.
30. Main classes of tumour antigens
â– Products of mutated oncogenes and tumour suppressor genes.
â– Products of other mutated genes.
â– Over expressed or aberrantly expressed cellular proteins.
â– Tumour antigens produced by oncogenic viruses.
â– Oncofetal antigens.
â– Altered cell surface glycolipids and glycoproteins.
â– Cell type-specific differentiation antigens.
31.
32. Products of mutated oncogenes and
tumour suppressor genes
â– Neoplastic transformation, results from genetic alterations in proto-
oncogenes and tumour suppressor genes; these mutated genes encode
variant proteins that have never been seen by the immune system and are
thus recognized as non- self.
â– They may enter the class I MHC antigen-processing pathway and be
recognized by CD8+ T cells. In addition, these proteins may enter the class
II antigen-processing pathway in antigen- presenting cells that have
phagocytosed dead tumour cells, and thus be recognized by CD4+ T cells
also.
33. Over expressed or aberrantly
expressed cellular proteins
â– Tumour antigens may also be normal cellular proteins that are abnormally
expressed in tumour cells.
â– It may be surprising that the immune system is able to respond to this
normal self-antigen. The probable explanation is that these antigens are
normally produced in such small amounts and in so few normal cells that it is
not recognized by the immune system and fails to induce tolerance.
â– One such antigen is tyrosinase, an enzyme involved in melanin biosynthesis
that is expressed only in normal melanocytes and melanomas.
34. Tumour antigens produced by
oncogenic viruses
â– Several viruses are associated with cancers. Not surprisingly, these viruses
produce proteins that are recognized as foreign by the immune system.
â– The most potent of these antigens are proteins produced by latent DNA viruses;
examples in humans include human papilloma virus (HPV) and Epstein-Barr
virus (EBV).
â– There is abundant evidence that CTLs recognize antigens of these viruses and
that a competent immune system plays a role in surveillance against virus-
induced tumours because of its ability to recognize and kill virus-infected cells.
â– In fact, the concept of immune surveillance against tumours is best established
for DNA virus- induced tumours.
36. TUMOUR ORGANISM
Adult T cell leukemia Human T Leukemia Virus I(HTLV I)
• Burkitt’s lymphoma & lymphoma in
immunosuppression
• Nasopharyngeal cancer
EBV
Cervical cancer Human papilloma virus (HPV 16 & 18 and
others)
Liver cancer Hepatitis B and C
Skin cancer Probably HPV
Gastric carcinoma Helicobacter pylori
37. Oncofetal antigens
â– Oncofoetal antigens are proteins that are expressed at high levels on cancer
cells and in normal developing (foetal) tissues.
â– Although originally believed to be completely specific for tumours and foetal
tissues, as techniques for detecting these antigens have improved, it became
clear that their expression in adults is not limited to tumours.
â– Amounts of these proteins are increased in tissues and in the circulation in
various inflammatory conditions, and they are even found in small
quantities in normal tissues.
â– There is no evidence that oncofoetal antigens are important inducers or
targets of antitumor immunity.
38. Oncofetal antigens
â– However, oncofoetal proteins are sufficiently specific that they can serve as
markers that aid in tumour diagnosis and clinical management.
â– The two most thoroughly characterized oncofoetal antigens are
carcinoembryonic antigen (CEA) and ⍺-fetoprotein (AFP).
39. Altered cell surface glycolipids and
glycoproteins.
â– Most human and experimental tumours express higher than normal levels
and/or abnormal forms of surface glycoproteins and glycolipids, which may
be diagnostic markers and targets for therapy.
â– Several mucins have been the focus of diagnostic and therapeutic studies,
including CA-125 and CA-19-9, expressed on ovarian carcinomas, and MUC-
1, expressed on both ovarian and breast carcinomas.
40. Cell type-specific differentiation
antigens.
â– Tumours express molecules that are normally present on the cells of origin.
These antigens are called differentiation antigens because they are specific
for particular lineages or differentiation stages of various cell types. Such
differentiation antigens are typically normal self-antigens, and therefore
they do not induce immune responses in tumour-bearing hosts.
â– Their importance is as potential targets for immunotherapy and for
identifying the tissue of origin of tumours.
41. Although the immune system clearly can respond
to tumour cells, the fact that so many individuals
die each year from cancer suggests that there are
several mechanisms by which tumour cells appear
to evade the immune system.
42. MECHANISMS DEVELOPED BY TUMOUR
CELLS TO EVADE
IMMUNOSURVEILLANCE.
Selective outgrowth
of antigen-negative
variants
Loss or reduced
expression of MHC
molecules
Activation of
immuno-regulatory
pathways
Immunosuppression Antigen masking
Induction of
regulatory T cells
(Tregs)
45. Down-regulation of
class I MHC expression
on tumour cells may
allow a tumour to
escape CTL-mediated
recognition.
46. Antigen masking
â– Presumably the antibody binds to tumour-specific antigens and masks the
antigens from cytotoxic T cells.
â– In many cases, the blocking factors are not antibodies alone but rather
antibodies complexed with tumour antigens.
â– The mechanism of this inhibition is not known.
â– The complexes also may inhibit ADCC by binding to Fc receptors on NK cells or
macrophages and blocking their activity.
47. Activation of immunoregulatory
pathways
■TH-cell recognition of an antigenic peptide–MHC complex sometimes results
in a state of non responsiveness called clonal anergy, marked by the inability
of cells to proliferate in response to a peptide-MHC complex.
â– This happens in the absence of a co-stimulatory signal, such as that
produced by interaction of CD28 on TH cells with B7 on antigen-presenting
cells.
â– Through various mechanisms, tumour cells may downregulate the
expression of co-stimulatory factors on APCs, making the tumour cell poorly
immunogenic.
48. Immunosuppression
â– Tumours may secrete several products that inhibit the host immune
response.
â– TGF-beta is secreted in large quantities by many tumours and is a potent
immunosuppressant.
â– Other such molecules secreted by tumour cells are : Galectins, Interleukin-
10, Prostaglandin E2, certain metabolites derived from Tryptophan And
VEGF.
49. some studies suggest
that tumors produce
factors that favor the
development of
immunosuppressive
regulatory T cells,
which could also
contribute to "immune
evasion."
50. TUMOUR CELL
SECRETION OF CD95/ FASL
ACTIVATION OF
EFFECTOR T
CELLS
ACTIVATION OF
EFFECTOR TREG
CELLS
DONOT
EXPRESS
C-FLIP
EXPRESS C-
FLIP
CELL DEATH ESCAPE CELL DEATH
SELECTIVE ACCUMULATION OF
IMMUNOSUPRESSIVE TREGS
51. SUMMARY
â– The immune system is a remarkably versatile defense system that has
evolved to protect animals from invading pathogens and cancer.
â– As conceptualized by Paul Ehrlich, as early as 1909, it is able to generate an
enormous variety of cells and molecules capable of specifically recognizing
and eliminating not only a variety of foreign invaders, but also a number of
aberrant cells arising from complex fetal and post- fetal development.
â– These cells and molecules act together in a dynamic network whose
complexity rivals that of the nervous system.
â– However, cancer continues to be one of the major causes of death worldwide,
meaning that the theory of immunosurveillance, albeit convincing, is not
entirely perfect.
â– Attempts on augmentation of the natural defense mechanisms of the body is
one major approach to making cancer a curable disease.
53. REFERENCES
â– Delves PJ, Martin SJ, Burton DR, Roitt IM. Essential immunology. Sixth
edition.John Wiley & Sons; 1988.
â– Owen JA, Punt J, Stranford SA.Kuby immunology.sixth edition. New York:
WH Freeman; 2006.
â– Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran pathologic
basis of disease. ninth edition. elsevier health sciences;2014.
â– Swann JB, Smyth MJ. Immune surveillance of tumors. The Journal of
clinical investigation. 2007 May 1;117(5):1137-46.
â– Ribatti D. The concept of immune surveillance against tumors: The first
theories. Oncotarget. 2017 Jan 24;8(4):7175- 7180.
Editor's Notes
James P Allison and Tasuku Honjo awarded nobel prize in2018 for their work in cancer immunotherapy.
JPA developed ipilimumab which is an antibody against CTLA-4, which is a molecule that competes with CD28 for the binding site B7.