4. Modern concepts in carcinogenesis
⢠viral etiology
⢠mutated onco-proteins
⢠over-expression normal antigens
⢠generation of antigen specific immune
responses
⢠sophisticated mechanisms
â triggering of multiple pathways
⢠impairment of T cell anti-tumor responses
6. Alterations of Immune Response in
cancer
⢠dysfunctional immune response
â loss of DTH
⢠âblocking antibodiesâ
⢠suppressor factors
⢠suppressor macrophages
⢠development of characteristic opportunistic
infections?
â T cell responses against bacterial and/or chemical
antigens
7. ability of Tumors to suppress T responses?
⢠failure of immunotherapy
â loss of T cell responses
⢠vaccine trials demonstrated progression of
tumors
â robust T cell response
⢠cellular and molecular models
â T cell anergy
8. discovery of several mechanisms
⢠role of immunoregulatory molecules in APC
â B7.1, B7.2, B7-H1 & B7-H4
⢠development of Tregs
⢠tumor-induced accumulation of MDSCs
⢠initiators of suppression
â tumor cells
â APCs(DCs & MďŚs)
â MDSC
9. Tumor cells?
⢠tumor cells produce
ď§ VEGF
ď§ G-CSF
ď§ GM-CSF
⢠arrested differentiation of myeloid cells
â block T cell responses
⢠IL-10, TGF-β & PGE2
⢠accumulation of immature myeloid cells
â head & neck, breast, and lung cancer
10. mechanisms by which T cells become
suppressed
⢠multiple, but discrete changes in expression of
â CD3Îś (H2O2)
â tyrosine kinases p56lck, p59fyn
â upregulate Jak-3
â translocate NFkBp65
⢠diminished ability to mobilize Ca++
⢠decreased tyrosine phosphorylation
ďśrenal cell carcinoma, melanoma, Hodgkinâs disease,
ovarian cancer, colon carcinoma, & cervical cancer
11. CD3Îś
⢠oxygen scavengers radicals (H2O2)
⢠increased number of activated neutrophils
⢠pancreatic & breast cancer
â chronic stimulation of T cells by specific antigens
12. Metabolism of L-Arg by Myeloid Cells
⢠L-Arg substrate for
â NOS1, NOS2, & NOS3
â Arginase I and II
â Arginine: glycine amidinotransferase (AGLT)
â L-Arg decarboxylase (ADC)
⢠dietary L-Arg is taken up by intestinal
epithelial cells
⢠transported via y+ system of cationic amino
acid transporters (CAT)
14. expression of arginase I and NOS2
⢠in murine macrophages
â differentially regulated
⢠Th1 & Th2 cytokines
â IFN-Îł up-regulates NOS2 exclusively
â IL-4, IL-10 and IL-13 induce arginase I
⢠arginase II
â mitochondrial isoform
â modulation by Th1 or Th2 cytokines?
16. Immunityâs Roles in Cancer Suppression &
Promotion
⢠immune system plays a dual role in cancer:
â suppress tumor growth
⢠by destroying cancer cells or inhibiting their
outgrowth
â promote tumor progression
⢠by selecting for tumor cells that are more fit to
survive in an immunocompetent host
⢠by establishing conditions within tumor
microenvironment that facilitate tumor outgrowth
16
17. Tumor immunology
⢠Can immune system control cancer?
â subject of debate for over a century
⢠Paul Ehrlich (1900)
âthat cancer would be quite common in long-
lived organisms if not for the protective effects
of immunityâ
⢠How?? 50 yrs
17
18. cancer immunosurveillance hypothesis
⢠Burnet and Thomas
â adaptive immunity was responsible for preventing
cancer development in immunocompetent hosts
⢠Stutman challenged this hypothesis
â similar susceptibility of immunocompetent &
nude mice
⢠largely abandoned
⢠why cancer immunosurveillance could not
possibly occur?
18
19. cancer immunosurveillance hypothesis
⢠âdanger signalsâ in tumor cells?
⢠ignorance or tolerance to a developing tumor
⢠persistent activation of innate, pro-
inflammatory arm of immunity
â facilitate cellular transformation & promote
cancer outgrowth
19
20. cancer immunosurveillance hypothesis
⢠improved mouse models of immunodeficiency on
pure genetic backgrounds
â reassess role of immunity in cancer control
⢠rekindled immunosurveillance hypothesis:
â IFNď§ inducing rejection of transplanted tumor cells
â mice lacking either IFNď§ responsiveness
⢠lacking either IFNď§ R or STAT1 transcription or adaptive
immunity [RAG2â/â]
â more susceptible to carcinogen induced & spontaneous primary
tumor formation
âthe immune system can function as an extrinsic
tumor suppressorâ
20
21. Immunityâs Roles in Cancer
⢠3 distinct roles in preventing cancer:
ďprotects host against viral infection
ďsuppresses virus-induced tumors
ďit prevents establishment of an inflammatory
environment
⢠tumorigenesis
⢠by eliminating pathogens & prompt resolution of
inflammation
ď it eliminates tumor cells in certain tissues
21
22. Tumor Antigens & Cancer Immunosurveillance
⢠fundamental tenet of tumor immunology in
general & of cancer immunosurveillance
â cancer cells express antigens
⢠differentiate them from their non-transformed
counterparts
⢠mice immunized with chemically induced
tumors
â protected against subsequent re-challenge with
same tumor
â âtransplantation rejection antigensâ
22
23. Tumor Antigens
⢠molecular studies revealed that these antigens
were
â products of mutated cellular genes
â aberrantly expressed normal genes
â genes encoding viral proteins
23
24. Tumor Antigens
⢠human tumor antigens include:
â differentiation antigens (melanocyte
differentiation)
â mutational antigens (such as p53)
â over expressed cellular antigens (such as HER-2)
â viral antigens (such as HPV proteins)
â cancer/testis (CT) antigens
24
25. The Cancer Immunoediting Hypothesis
⢠The discovery in 2001
âthe immune system controls not only tumor
quantity but also tumor quality
(immunogenicity)â
⢠prompted a major revision of cancer
immunosurveillance hypothesis
25
27. The Cancer Immunoediting Hypothesis
⢠the immune system not only protects host
against tumor formation but also shapes
tumor immunogenicity is basis of cancer
immunoediting hypothesis
⢠stresses dual host-protective & tumor-
promoting actions of immunity on developing
tumors
27
28. The Cancer Immunoediting Hypothesis
⢠cancer immunoediting process
⢠in its most complex embodiment, proceeds
sequentially through 3 distinct phases:
â âeliminationâ
â âequilibriumâ
â âescapeâ
28
29. The Cancer Immunoediting Hypothesis
⢠in some cases tumor cells may directly enter
into either equilibrium or escape phases
⢠external factors may influence directionality of
flow:
â environmental stress
â immune system deterioration accompanying aging
â immunotherapeutic intervention on tumor cell
outgrowth in human cancer patients
29
31. Elimination pahse
⢠transformed cells
â develop after failure of intrinsic tumor suppressor
mechanism
â initiate stromal remodeling which results in local
tissue disruption
â recognized as a danger signal by cells of innate
immune system
⢠NK cells, NKT, γδ T cells & macrophages
⢠interaction of these cells triggers extrinsic tumor
suppressive mechanism:
â generation of IFN-Îł and ILs by NK cells and macrophages
31
32. Elimination phase
⢠INF-γ activates
â antiproliferative, proapoptotic & angiostatic
processes
â lead to death of a significant number of tumor
cells
⢠Macrophages by production of ROS & RNI
⢠NK cell via TRAIL or perforin dependent
mechanisms
â together kill the residual tumor cells
32
33. Elimination phase
⢠killing generates tumor antigens which
activate DCs recruited at the tumor site
⢠DC capture tumor antigens & migrate to LNs
â activate naĂŻve Th1 CD4+ T cells
â CD8+ cytotoxic lymphocytes (CTL)
â tumor specific CD4+ and CD8+ T cells
⢠migrate to tumor site to kill viable antigen positive
tumor cells
33
34. Elimination phase
⢠CD4+ T cells produce IL-2
â keeps tumor specific CD8+ T cells activated
⢠CD8+ T cells recognize
⢠kill the tumor cells directly
â by IFN-Îł dependent mechanisms of cell cycle
inhibition, apoptosis, and angiostasis
â by induction of macrophage tumoricidal
34
36. Does the Equilibrium Phase Really Exist?
⢠explain the period of immune dormancy
experienced
⢠phenomenon of relapse seen in many cancers
after one to two decades of remission
⢠immune system controlling, but not
eliminating
36
37. Evidences to equilibrium phase of cancer
⢠occurrence of minimal residual disease (MRD)
in leukemia and some solid malignancies lends
further support to equilibrium hypothesis
⢠MRD
â small number of malignant cells remain in body
below threshold of conventional morphologic or
cytogenetic recognition
37
38. Evidences to equilibrium phase of cancer
⢠preneoplastic conditions like monoclonal
gammopathy of undetermined significance
(MGUS)
⢠existence of an immune response to
premalignant MGUS cells that eventually
progress to multiple myeloma (MM)
38
39. What are the Mechanisms Involved in
Equilibrium?
⢠solely maintained by adaptive immunity in
contrast to the other two phases
â significant reduction in tumor progression in case
of infiltration of tumor by the T lymphocytes
â extent of involvement of CD4+CD25+Foxp3+ T
cells or Treg???
â role of cytokines like IFN-Îł and TNF has also been
suggested by some studies
39
40. Evidences to equilibrium phase of cancer
⢠immunogenicity of cancer cells also varies
during the three stages
â more immunogenic in equilibrium phase
⢠Where do they hide?
â reside in ânichesâ made up of specialized vascular
bed of endothelial cells, associated stromal cells of
mesenchymal origin & extracellular matrix
components
40
42. How does Tumor Evade Equilibrium?
⢠by complex interplay of cancer cells, the
cytokines and the immune cells
⢠the tumor
â sheds all its antigens & other molecules which
immune cells use for their recognition i.e. MHC,
NKG2D
â tumor cells which in turn induce CTLA-4
â immuno suppresive state is accentuate by
secretion of cytokines like TGF-β and IL-10
42