Cancer cells are sneaky. They use various tricks to hide from our immune system, making it hard for our body to fight them off. These evasion strategies include changing their surface molecules, releasing chemicals that suppress immune responses, and recruiting cells that dampen our defenses.

Tumors create a hostile environment for immune cells. They produce substances that inhibit T cells, bring in suppressive cells like Tregs and MDSCs, and express molecules that exhaust our immune fighters. Understanding these tactics is crucial for developing better cancer treatments.

Tumor Immune Evasion Strategies

Tumor immune evasion strategies

• Alteration of tumor cell surface molecules hinders immune recognition
  • Downregulation of MHC class I expression reduces antigen presentation to CD8+ T cells
  • Loss of tumor-associated antigens (melanoma antigens) makes tumor cells less visible to immune system
• Secretion of immunosuppressive factors dampens immune responses
  • Cytokines TGF-β and IL-10 suppress T cell activation and proliferation
  • Prostaglandin E2 (PGE2) inhibits T cell function and promotes tumor growth
• Recruitment of immunosuppressive cells creates hostile environment for effector immune cells
  • Regulatory T cells (Tregs) suppress anti-tumor immune responses
  • Myeloid-derived suppressor cells (MDSCs) inhibit T cell activation and produce immunosuppressive molecules
• Expression of immune checkpoint molecules induces T cell exhaustion
  • PD-L1 on tumor cells binds to PD-1 on T cells, inhibiting their function
  • CTLA-4 ligands (CD80/CD86) on antigen-presenting cells compete with CD28 for T cell activation
• Induction of T cell exhaustion leads to dysfunctional tumor-specific T cells
• Creation of hypoxic tumor microenvironment impairs immune cell function
• Metabolic reprogramming of tumor microenvironment starves immune cells
  • Depletion of essential amino acids (tryptophan) inhibits T cell proliferation
  • Accumulation of immunosuppressive metabolites (adenosine) suppresses T cell responses

Immunosuppression in tumor microenvironment

• Immunosuppressive cytokines create hostile environment for effector immune cells
  • TGF-β inhibits T cell proliferation and effector functions, promoting tumor growth
  • IL-10 suppresses antigen presentation and T cell activation, weakening anti-tumor responses
  • IL-35 promotes regulatory T cell expansion, further suppressing immune responses
• Regulatory T cells (Tregs) actively suppress anti-tumor immunity
  • Recruitment to tumor site increases local immunosuppression
  • Suppression of effector T cell functions through direct contact and cytokine production
  • Production of immunosuppressive cytokines (TGF-β, IL-10) amplifies suppressive effects
  • Consumption of IL-2 deprives effector T cells of crucial growth factor
  • Induction of anergy in tumor-specific T cells renders them unresponsive
• Myeloid-derived suppressor cells (MDSCs) contribute to immunosuppression
  • Inhibition of T cell activation and proliferation through various mechanisms
  • Production of reactive oxygen species (ROS) and nitric oxide (NO) impairs T cell function
• Tumor-associated macrophages (TAMs) support tumor growth and suppress immunity
  • Promotion of tumor growth and angiogenesis through growth factor production
  • Suppression of anti-tumor immune responses by producing immunosuppressive factors

Immune checkpoints in tumor escape

• CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) inhibits T cell activation
  • Competes with CD28 for binding to CD80/CD86, outcompeting costimulatory signals
  • Inhibits T cell activation and proliferation, reducing anti-tumor responses
  • Expressed on activated T cells and Tregs, amplifying immunosuppression
• PD-1 (Programmed cell death protein 1) induces T cell exhaustion
  • Binds to PD-L1/PD-L2 on tumor cells or antigen-presenting cells, transmitting inhibitory signals
  • Induces T cell exhaustion and apoptosis, reducing tumor-specific T cells
  • Inhibits T cell effector functions, weakening anti-tumor immunity
• Other checkpoint molecules contribute to immune suppression
  • LAG-3 inhibits T cell activation and function, particularly CD4+ T cells
  • TIM-3 promotes T cell exhaustion and dysfunction
  • VISTA suppresses T cell responses through multiple mechanisms
• Therapeutic implications highlight importance of checkpoint molecules
  • Checkpoint inhibitors (anti-PD-1, anti-CTLA-4) revolutionize cancer immunotherapy
  • Combination therapies targeting multiple checkpoints show enhanced efficacy

MHC downregulation for T cell evasion

• Mechanisms of MHC class I downregulation reduce antigen presentation
  • Mutations in β2-microglobulin gene disrupt MHC class I assembly
  • Defects in antigen processing machinery components (TAP, tapasin) impair peptide loading
  • Epigenetic silencing of MHC class I genes reduces overall expression
• Consequences of MHC class I downregulation aid tumor immune escape
  • Reduced recognition by CD8+ T cells limits tumor cell killing
  • Escape from immune surveillance allows tumor growth and progression
• Alterations in antigen processing and presentation further hinder T cell recognition
  • Defects in proteasome subunits (LMP2, LMP7) alter peptide generation
  • Impaired function of TAP (Transporter associated with antigen processing) reduces peptide transport
  • Reduced expression of costimulatory molecules weakens T cell activation
• Selective loss of tumor-associated antigens makes tumors less visible
  • Antigenic drift through mutations in antigen-encoding genes creates immune escape variants
  • Downregulation of antigen expression reduces targets for immune recognition
• Implications for immunotherapy highlight challenges and opportunities
  • Challenges in developing effective T cell-based therapies due to antigen loss
  • Potential for NK cell-based approaches to target MHC class I-low tumors