11.2 Cancer and the Immune System

The Immune System and Cancer

• Cancer results from imbalances in cell division and death rates
• Tumors form when cells divide faster than they die
• Development of tumors: Carcinogens, radiation, viral infections, chronic inflammation, and genetic mutations can cause cells to transform
• Intrinsic tumor suppression mechanisms often eliminate early-stage tumors; however, some survive

Tumor Antigens

• Tumor-specific antigens are only present on tumor cells
• Tumor-associated antigens are found on both normal and tumor cells

Immune Response to Tumors

• Innate Immune Mechanisms
  • Neutrophils produce TNF-related apoptosis-inducing ligand (TRAIL), triggering apoptosis in tumor cells
  • Natural Killer (NK) cells express NKG2D, which binds to MICA and MICB on tumor cells, initiating apoptosis.
• Macrophages
  • Classically activated M1 macrophages kill tumor cells
  • Tumor cells may be recognized by damage-associated molecular patterns (DAMPs) released by dying tumor cells, activating macrophages.
  • IFN-γ, produced by tumor-specific T cells, activates macrophages, triggering nitric oxide (NO) production to kill tumor cells.
  • M2 macrophages promote tumor growth by secreting vascular endothelial growth factor (VEGF) and TGF-β
• Adaptive Immune Mechanisms
  • CD8+ T cells directly destroy tumor cells using perforins and granzymes
  • CD4+ T cells activated by antigen-presenting cells (APCs) contribute to direct or indirect tumor destruction.
  • IFN-γ, produced by CD4+ T cells, activates macrophages
  • Natural Killer T (NKT) cells target tumor cells displaying non-classical MHC class I molecules
• Antibodies
  • Antibodies produced by tumor-bearing hosts can target tumor antigens, activating complement or mediating antibody-dependent cell-mediated cytotoxicity (ADCC)

Tumor Escape

• Some tumors actively suppress host immune responses
• TGF-β induces tumor cell proliferation and angiogenesis
• TGF-β suppresses anti-tumor immune responses
• Tumor-activated dendritic cells (DCs) secrete indoleamine 2,3-dioxygenase (IDO), inhibiting T cell proliferation
• Tumor cells often secrete galectin-1, stimulating angiogenesis
• Programmed cell death ligand 1 (PD-L1), secreted by tumor cells, slows immune responses

Mechanisms by which Tumors Escape T Cell Immune Defenses

• Failure to produce tumor antigens
• Loss of tumor antigens
• Mutations in MHC genes/antigen processing pathways
• Lack of T cell recognition
• Secretion of immunosuppressive proteins
• Expression of inhibitory cell surface proteins (e.g., PD-L1)

Equilibrium

• Tumor cells can maintain a steady state without progressing
• Tumor cells are not completely eliminated, nor do they fully proliferate

Tumor Immunoediting

• Tumor cells under sustained immune pressure may be edited by the adaptive immune system
• Tumor cells growing without an adaptive immune system remain immunogenic

Cancer Immunoediting

• Cells undergoing transformation release danger signals, which trigger intrinsic tumor suppression.
• Equilibrium (persistence and dormancy) occurs when the immune system and tumor cells reach a balance.
• Escape (cancer progression) occurs when suppression mechanisms fail and tumors resume growth.

Immune Evasion

• Failure to produce tumor antigens, loss of tumor antigens
• Mutations in MHC genes or antigen processing genes
• Lack of T cell recognition
• Secretion of immunosuppressive proteins; expression of inhibitory cell surface proteins

Tumor Immunotherapy

• Nonspecific immune stimulation (microbial products, cytokines)
• Passive immunization (monoclonal antibodies)
• Active immunization (chemically modified tumor cells, DNA vaccines, vaccines against oncogenic viruses)

Adoptive Transfer of In Vitro Activated Immune Cells

• In vitro activated lymphocytes are transferred to the patient to fight tumor cells

T Cell Inhibitor Blockade

• Blocking PD-L1/PD1 interactions on tumor cells enables T cell activation, leading to tumor cell destruction.