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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