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TUMOUR IMMUNOLOGY
Sukchai Satthaporn MD. PhD.Department of Surgery
Pramongkutklao Hospital and College of Medicine
Contents
• Immunosurveillance• Effector mechanisms in anti-tumour
immunity• Mechanisms of tumour evasion of the
immune system• Immunotherapy for tumours
Immunosurveillance
• An hypothesis states physiologic function of the immune system is to recognize and destroy malignantly transformed cells before they grow into tumours
• Implies that cells of the immune system recognize something “foreign” on transformed/tumour cells
Proposed by Paul Ehrlich, Macfarlane Burnet and Lewis Thomas
Immunosurveillance
• The immune system has evolved in all species mainly to fight and prevent foreign invasions from infectious pathogens
• Immune system can also respond against internal attacks such as those resulting from malignant transformation
Evidence in Support of Immunosurveillance (I)
• Immunodeficient individuals are more likely to develop certain types of tumoursthan immunocompetent individuals- Congenital immune deficiency- AIDS associated tumours- Transplantation recipients
Evidence in Support of Immunosurveillance (II)
• Clinicopathologic correlations suggest that lymphocytic infiltrates in some tumours(e.g. medullary breast carcinoma, malignant melanoma) are associated with a better prognosis compared to histologically similar tumours without infiltrates
Tumour Infiltrating Lymphocytes(TILs) and Macrophages (TIMs)
Evidence in Support of Immunosurveillance (II)
• Histologic evidence indicates that active immune responses occur within tumoursor in draining lymph nodes
Tumour Draining Lymph Node
Evidence in Support of Immunosurveillance (III)
• There is evidence that T and B lymphocytes specific for tumour surface molecules have been activated and expanded in tumour patients but hyporeactivity
Tumour Draining LN Lymphocyte Hyporeactivity
Spontaneous Regression of Cancer
• Number of cases: (Index Medicus and Cancer Lit: 1966-1987)• Leukemia/Lymphoma 124• Melanoma 69• Renal cell cancer 68• Neuroblastoma 41• Gastrointestinal cancer 34• Retinoblastoma 33• otal: 504• Lung and Bronchus 25• Breast 22• Testis 16• Head and neck (sq. cell) 8• Other 64
Immunosurveillance
• Classic experiments by Gross in the 1940’s demonstrating that mice that rejected a syngeneic murine sarcoma, developed protective immunity to subsequent injections of the same tumour
• Gross L. Cancer Research 3:326,1943; Prehn R. JNCI 18:769, 1957
Figure 14-10
Mechanisms of Tumour Killing
Eremin O and Sewell H. The Immunological Basis of Surgical Science and Practice. 1992.
Mechanisms in tumour Immunity
HumoralOpsonization and phagocytosis
Complement-mediated lysis
Loss of cell adhesion (antibody
dependent)
Cell-Mediated CytotoxicityT Cell (CTLs)
Antibody-dependent cytotoxicity
NK
LAK (lymphokine-activated killer) cells
Macrophages (macrophages can be activated by lymphokines)
Figure 14-13
Antibodies
• activity demonstrated mainly in vitro• most tumour-specific antigens do not elicit antibody responses in vivo
Activated macrophages
• activity demonstrated mainly in vitro• Tumour cells may be more susceptible to
macrophage-mediated killing than normal cells
NK cells
• Recognize lack of normal self class I MHC on some tumors
• Kill tumor cells in vitro by aperforin/granzyme granule exocytosismechanisms similar to CTLs
• May be defense against tumors which have escaped CTL killing
Figure 8-22 part 1 of 2
A B
Figure 8-31
Mechanisms of Tumour Evasion of the Immune System
Tumour Evades Host Immune System
• Tumours can evade the immune response by manipulating these pathways-TRICKY!!
• We need to manipulate the host immune system to overcome the tumour’s tricks
• Rammensee H. Immunogenetics 50:213, 1999; Greenberg PD. Advances in Immunology 49:281, 1991
Figure 14-14
Immunotherapy
• Active immunotherapy–Specific–Non-specific
• Passive immunotherapy–Specific–Non-specific
Active Specific Immunotherapy
Active Non-specific Immunotherapy
• Stimulated by the local administration of inflammatory substances or by systemic treatment with agents that function as polyclonal activators
• Activate macrophages or stimulate T cell responses
• Bacillus Calmette-Guerin (BCG) : carcinoma of the bladder
Passive Specific Immunotherapy
Passive Non-specific Immunotherapy
• Adoptive cellular immunotherapy– Isolate lymphocytes from blood or tumour
infiltrate– Expand lymphocytes by culture in IL-2
lymphokine-activated killer (LAK) cells – Transfer LAK cells into patient, with or
without systemic IL-2
Passive Non-specific Immunotherapy
• Cytokine Immunotherapy– Tumor necrosis factor (TNF): Rx of sarcomas– Type I interferons (IFN-a/b): Approved for
chronic myleoid and hairy cellleukemias, AIDS-related Kaposi’s sarcoma
– Interleukin-2: Rx for reanl cell carcinoma and melanoma
Anti-Tumour Vaccines
• Goal: To boost weak cell-mediated immune responses to tumor antigens
• Both helper T cell and CTL responses
Anti-Tumour Vaccines
• Form of vaccine– Peptides– Dendritic cells pulsed with tumor peptides– Cells expressing recombinant genes
encoding tumor antigens– DNA encoding tumor antigens
Thank you for your attention