the battle between immune response and cancer.

1. IMMUNE SUEVEILLANCE AND
IMMUNOLOGY OF MALIGNANCY
The battle between immune system
and cancer!!
CANCER

2.  GUIDED AND MOTIVATED BY:
Dr. Hema Suryawanshi
Dr. Akshay Dhobley
Dr.Pramod Sharma
Dr. Rolly Gupta
Presented by:
Neha Gupta PG 2nd yr

3.  Prologue
 Timeline
 Cancer immunoediting
 Studies
 Cytolytic capacity
 Patrolling transformation
 Tumour antigens
 Equilibrium phase
 Escape phase
 Immunotherapy
 Conclusion
 References

4.  BASIC KNOWLEDGE OF CANCER
• What is Cancer?
• How does cancer occur?
• How many types of cancers?
• Current therapeutic strategies for cancers

5.  Cancer consists of single clones or several
clones of cells that are capable of independent
growth in the host.
 Cancer cells arise from host cells via
neoplastic transformation or carcinogenesis.
 Physical, chemical and biological agents may
cause cancer.

6.  Physical
 Chemical
 Biological
 Hereditary

8. CANCER
IMMUNOSURVEILLANCE

9.  The last fifteen years have seen a reemergence of
interest in cancer immunosurveillance and a
broadening of this concept into one termed cancer
immuno- editing. The latter, supported by strong
experimental data obtained by studying human
cancer, holds that the immune system not only
protects the host against development of primary
nonviral cancers but also sculpts tumour
immunogenecity.

10.  Comments made decades ago by the architects of the
cancer immunosurveillance hypothesis, Burnet and
Thomas, that “there is little ground for optimism about
cancer”(Burnet,1957) and “the greatest trouble with the
idea of immunosurveillance is that it cannot be shown
to exist in experimental animals” (Thomas, 1982).
 With the development of mouse tumor models using
inbred mice with molecularly defined immunodefi-
ciencies, it has become possible to demonstrate the
existence of a cancer immunosurveillance process that
can prevent primary tumor growth.

11.  In 1909, Paul Ehrlich predicted that the immune system
repressed the growth of carcinomas that he envisaged
would otherwise occur with great frequency.
 Fifty years later as immunologists gained an enhanced
understanding of transplantation and tumor
immunobiology and immunogenetics, F. Macfarlane
Burnet and Lewis Thomas revisited the topic of natural
immune protection against cancer .
 Burnet believed that tumor cell-specific neo-antigens could
provoke an effective immunologic reaction that would
eliminate developing cancers (Burnet,1957,1964,1971).

12.  Thomas theorized that complex long-lived
organisms must possess mechanisms to protect
against neoplastic disease similar to those
mediating homograft rejection (Thomas, 1959).
 Old and Boyse, 1964:stated that sentinel thymus
dependent cells of the body constantly surveyed
host tissues for nascently transformed cells .

13.  Stutman, 1974-1979: new studies fueled by tech
nologic advances in mouse genetics and monoclonal
antibody (mAb) production—reinvigorated and ulti
mately validated the cancer immunosurveillance
concept.
 Smyth et al., 2001b; Dunn et al., 2002, 2004
expanded it to incorporate the contributions of both
innate and adaptive immunity,

14.  However, there has been a growing recognition that
immunosurveillance represents only one dimension
of the complex relationship between the immune
system and cancer (Dunn et al., 2002, 2004;
Schreiber et al., 2004).
 Recent work has shown that the immune system
may also promote the emergence of primary tumors
with reduced immunogenicity that are capable of
escaping immune recognition and destruction
(Shankaran et al).

15.  These findings prompted the development of the
cancer immunoediting hypothesis to more broadly
encompass the potential host-protective and tumor-
sculpting functions of the immune system throughout
tumor development (Dunn et al., 2002, 2004).

16. ELIMINATION
EQULIBRIUM
ESCAPE

20.  1st phase: antitumour immune response
 2nd phase: limited tumour death
 3rd phase: apoptosis
 4th phase: destruction of remaining antigen bearing
tumour cells

22.  Rapid accumulating data have begun to elucidate that
lymphocytes of both the adaptive and innate immune
compartments prevent tumour development.
 Lymphocytes expressing rearranged antigen
receptors play critical roles in the cancer
immunosurveillance process.

25.  RAG-2 -/- mice injected with chemical carcinogen
MCA ,the mice developed sarcomas at the injection
site faster and with greater frequency than strain
matched with wild type controls.
 NK and NKT cells also participate in cancer
immunosurveillance . Mice depleted of both NK and
NKT cells by using the anti NK1 were 2-3 times
more prone to MCA induced tumourogenesis.

26.  A recent provocative study by Cui et al. (Cui et al.,
2003)provides further evidence that innate immune
cells comprise an important arm of the
immunosurveillance network.
 A single mouse was serendipitously found that
failed to form ascites when injected intraperitoneally
with the extremely aggressive S180 sarcoma cell
line.

27.  Subsequent breeding revealed that the
obtained served cancer resistance trait was
germline transmisslble and was likely
controlled by a single autosomal dominant
locus.

28.  These data taken together highlight roles of both
innate and adaptive immunity in the elimination
phase of cancer immunosurveillance.
 Cancer immunosurveillance appears to be a
multivariable process in which immunologic
responses are influenced by a tumour’s cellular
origin,anatomic location,stromal response,cytokine
production profile,and inherent immunogenecity.

29.  The second critical effector function of cancer
immunosurveillance is the immune system’s ability
to kill tumor cells.
 Early studies identified perforin (pfp) as a critical
cytolytic molecule in the primary host antitumor
response.
 Subsequent studies revealed an important role for the
TNF-related apoptosis-inducing ligand(TRAIL)and
have underscored the importance of cytotoxicity
manifest by innate immunity in immunosurveillance.

31.  How cells of the immunosurveillance network
distinguish nascent transformed or established tumor
cells from normal cells?
 CD4 and CD8T cells recognize tumor antigens in the
context of MHC class II and class I proteins,
respectively.

32.  Tumor antigens are processed and presented to the
adaptive immune system as short peptide fragments
known as epitopes on major MHC class I and MHC class
II molecules. The MHC class I molecules are expressed
by nearly all nucleated cells of the body, and normally
present peptides that are generated endogenously in the
cells. It is imperative that the cancer cell presents some
form of immunogenic antigen in order for the CD8+
CTLs to recognize the tumor cell and destroy it.

33.  The CD8+T-cells are the key effectors of antitumor
immunity mediated by the adaptive immune system,
and they recognize antigenic epitopes presented in
the context of MHC class I molecules.
 CD4+ Th cells also play an important role in
antitumor immunity, as they enhance and amplify the
immune response through costimulation and the local
production of cytokines

34. DIFFERENTIATION ANTIGENS
MUTATIONALANTIGENS
OVEREXPRESSED ANTIGENS
CANCER-TESTIS ANTIGENS
VIRALANTIGENS

35.  Mutational antigens are derived from ubiquitous
proteins that are mutated in tumor cells. Point
mutations, chromosomal translocations, deletions, or
gene insertions can lead to the generation of unique
tumor antigens distinct for each tumor. The
mutational antigens are highly tumor-specific, and
some may also be involved in the transformation
process.

36.  Shared tumor-specific antigens are antigens whose
expression is usually silenced in normal tissues but
are activated in tumors of various histological types.
Expression of these antigens on normal tissues has
only been detected on placental trophoblasts and
testicular germ cells that do not express MHC class I
molecules.

38.  Differentiation antigens lack the specificity of tumor-
specific shared antigens, as they are differentiation
markers that are expressed not just by the malignant
cells, but also by the normal cells of the same origin
as the cancer cells. Tyrosinase, for example is
expressed by both normal melanocytes and most
melanoma cells.

39.  T-cell activation is dependent on a minimum number
of T-cell receptor/peptide/MHC contacts ; therefore,
the overexpression of many proteins in cancer cells
could lead to the generation of an immune response
to these self-proteins.
 The high levels of mutant or wild-type p53
expressed in many cancers make it a potential
immunotherapy target, and it has been used against
colorectal cancer without inducing autoimmunity

41.  Viral antigens are foreign and are only found on
infected cells, thereby making them ideal targets
because of their high specificity.
 The human papilloma virus (HPV) E6 and E7
proteins interfere with normal cell-cycle regulation
and are required for the viral life cycle.

42.  In addition to tumor antigens presented on MHC
molecules, transformed cells may over express other
molecular signposts that can function as recognition
targets in the immunosurveillance process.
 Several studies have pointed to the NKG2D-
activating receptor, expressed on NK cells, Υδ T
cells, and CD8 αβ T cells as one important
component that is used by both adaptive and innate
immune cells to distinguish cancer cells from normal
cells.

43.  Recent Findings have showed that tumours formed in
an immunodeficient environment are as a group more
immunogenic than tumours that develop in immuno
competent hosts.
 This concept recognises that even after escaping
immunosurveillance a tumour’s immunogenic
phenotype is continuously shaped by the
immunological forces in its environment.

44.  Based on the experimental systems there exists a
period of latency extending from the end of
elimination phase to the beginning of the escape
phase and the emergence of clinically detectable
malignant disease.

49.  Stealth and camouflage:escaping immunodetection
In order to escape successfully both arms of the
immune system, cancer cells have evolved a joint
strategy of both stealth and camouflage. They have to
hide the tumor antigens they express and disguise
themselves as something that the body will not reject.
The fetus is an allograft that survives within the
maternal host despite its low expression of allogenic
MHC molecules . The same immune evasion strategies
utilized by the fetus “camouflage” the cancer cells and
enable them to escape the NK cells.

51.  In order to escape NK-mediated killing, cancer cells
have evolved to establish tolerance using similar
mechanisms as those found in fetal–maternal
interactions. HLA-G is a nonclassical MHC class I
molecule expressed in the placenta and helps to
maintain tolerance to the fetus. It is expressed by
many cancers like melanoma, renal carcinoma, lung
carcinoma, glioblastoma, and ovarian cancer.

53.  Cancer cells are basically self-cells that are no longer
regulated by normal cellular processes and proliferate
without control. These aberrant cells are predisposed
to accumulating genetic errors that place them in a
better position to adapt to changes in their
environment.
 Like organisms predicted by Darwin’s Theory of
Natural Selection to adapt to the environment or
suffer extinction, immune pressure selects for tumor
variants that are resistant to immune eradication.

54.  Apart from the immune evasion strategies listed,
modulation of the immune response to incapacitate
the antitumor response is a powerful evolutionary
adaptation of the cancer cells.
 Most of the immunomodulatory mechanisms found
in tumors are based on normal homeostatic control
processes of the immune response set in place to
prevent unbridled proliferation of the immune cells,
or to maintain tolerance towards self-tissues.

55.  The intercellular adhesion molecule (ICAM)-1 is
crucial for the formation of the immunological
synapse.
 ICAM-1 participates in the cell–cell interaction
between the NK cell and the malignant cell.
 Transformed cells have been shown to disrupt this
cellular interaction by producing the matrix
metalloproteinase 9, which results in ICAM-1
shedding and resistance to NK cell killing

58.  CD40 has been detected on a variety of human
cancer cells, from various origins such as bladder,
ovarian, colorectal, liver, lung, pancreas, prostate,
cervical, and breast .
 It has been shown that CD40 activation on bladder
and human gastric carcinoma cells inhibits apoptosis
mediated through Fas using a similar mechanism to
the one in the B-cell apoptosis rescue.

59.  In addition, CD40 activation is able to induce an
increase in the motility of gastric carcinoma cells,
and its expression has been detected in the tumor
vasculature of renal and breast carcinoma as well as
in Kaposi’s sarcoma , suggesting a potential role of
CD40 in the angiogenesis and metastasis of cancer.

62.  TGF-β is commonly overexpressed in many cancers
and has many immunosuppressive effects, including
the inhibition of T-cell proliferation and their
development into CTLs and Th cells .
 TGF-β-overexpressing tumors are particularly
aggressive, and have been correlated with a more
malignant phenotype.

64.  Allies or enemies??

65.  Tumors have evolved ways to become resistant to
the death effector mechanisms, thereby becoming
truly impervious to immune attack.
 The perforin/granzyme and Fas/FasL pathways are
the two main effector mechanisms by which CTLs
and NK cells mediate antitumor immunity

68.  Bcl-2 and Bcl-Xl

70. VEGF is a key mediator in both vasculogenesis and
angiogenesis .
VEGF expression is associated with poor prognosis
and increased metastatic spreading in ovarian cancer.
In addition, VEGF also inhibits T-cell development
and contributes to tumor-mediated immune
suppression

78. ..VideosHypernature video

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