How does the immune system patrol for cancer?

How the Immune System Patrols for Cancer

The immune system patrols for cancer through a complex interplay of innate and adaptive immune components that recognize and respond to tumor-associated antigens, with cytotoxic CD8+ T cells and natural killer cells playing central roles in tumor surveillance and elimination. 1, 2

Key Components of Immune Surveillance

Innate Immune System Components

• Natural Killer (NK) Cells: These cytotoxic innate lymphocytes spontaneously detect and lyse transformed or stressed cells without prior sensitization 2
• Dendritic Cells (DCs): Function as "nature's adjuvants" by capturing tumor antigens and presenting them to T cells, bridging innate and adaptive immunity 3
• Macrophages: Can polarize toward either protumorigenic (M2) or antitumorigenic (M1) functional phenotypes, with their activity regulated by T lymphocytes 1
• Myeloid-Derived Suppressor Cells: Can shape the microenvironment toward either an immunostimulatory antitumor milieu or a wound-healing tumor-promoting environment 1

Adaptive Immune System Components

• CD8+ T Cells: Extensive tumor infiltration by cytotoxic CD8+ T cells is strongly associated with patient survival and response to therapy 1
• CD4+ T Cell Subsets:
  • Th1 cells: Associated with favorable clinical outcomes through interferon-γ production 1
  • Th2 cells: Generally associated with dampening antitumor responses 1
  • Follicular helper cells (Tfh): Positively associated with patient outcomes in both adjuvant and neoadjuvant settings 1
  • Regulatory T cells (Treg): Can have both positive and negative effects on antitumor immunity 1
• B Cells: Their precise role remains controversial but they contribute to the adaptive immune response 1

The Cancer-Immunity Cycle

1. Antigen Recognition: The immune system detects tumor cells through:

   • Tumor Neoantigens (TNAs): Novel antigens not covered by central tolerance 1
   • Tumor-Associated Antigens (TAAs): Self-antigens for which central tolerance is leaky 1
   • Post-Translational Modifications: Can generate antigenic determinants 1

2. Danger Signal Detection: Dying cancer cells emit damage-associated molecular patterns (DAMPs) that:

   • Alert the immune system to cellular damage
   • Activate pattern recognition receptors (PRRs) on antigen-presenting cells 1
   • Support recruitment and maturation of antigen-presenting cells 1

3. Antigen Processing and Presentation:

   • Dendritic cells capture tumor antigens
   • DCs migrate to lymph nodes
   • DCs present antigens to T cells, initiating adaptive immunity 1, 3

4. T Cell Activation and Expansion:

   • Naïve T cells recognize presented antigens
   • Clonal expansion of tumor-specific T cells occurs
   • Differentiation into effector T cells 1

5. Trafficking and Infiltration:

   • Activated T cells migrate to tumor sites
   • Tumor-infiltrating lymphocytes (TILs) enter the tumor microenvironment 1

6. Recognition and Elimination:

   • Cytotoxic T cells recognize tumor cells
   • NK cells detect stressed or transformed cells
   • Tumor cell killing through release of lytic molecules 1, 2

Tumor Microenvironment Influence

The effectiveness of immune surveillance is significantly affected by the tumor microenvironment:

• TIL-rich vs. TIL-poor tumors: Reflect distinct tumor biology with different susceptibility to immunotherapy 1
• Tertiary Lymphoid Structures (TLS): In moderately to extensively infiltrated tumors, these organized immune structures may signal the generation of immunological memory 1
• Tumor Heterogeneity: Variability within individual tumors suggests that tumor-immune interactions may parallel tumor heterogeneity 1

Immunoediting Process

Cancer immunosurveillance operates through a process called immunoediting, which consists of three phases 1:

1. Elimination: The immune system successfully detects and destroys emerging tumor cells
2. Equilibrium: Tumor cells and immune system reach a balance where tumor growth is controlled but not eliminated
3. Escape: Tumor cells develop mechanisms to evade immune detection and elimination, allowing progression

Immune Evasion Mechanisms

Tumors develop various strategies to evade immune surveillance:

• Downregulation of tumor antigens
• Expression of immunosuppressive molecules
• Recruitment of immunosuppressive cells like Tregs and MDSCs
• Creation of a metabolically hostile microenvironment
• Upregulation of immune checkpoint molecules (PD-1/PD-L1, CTLA-4) 4

Clinical Implications

Understanding immune surveillance mechanisms has led to several therapeutic approaches:

• Immune Checkpoint Inhibitors: Target PD-1, PD-L1, CTLA-4 to reinvigorate exhausted T cells 4
• Adoptive Cell Therapies: Including CAR-T cells and expanded TILs 4
• Cancer Vaccines: Utilize dendritic cells to present tumor antigens 3
• Combination Approaches: Chemotherapy and radiotherapy may "jump start" the immune system by promoting immunogenic cell death 1

Biomarker Development

Assessment of tumor-infiltrating lymphocytes (TILs) has emerged as a prognostic and predictive biomarker:

• TILs assessment: The degree of lymphocytic infiltration in H&E-stained tumor sections has predictive value in triple-negative and HER2+ breast cancers 1
• Stromal TILs: Evaluation of the stromal compartment has shown to be more reproducible between studies 1
• Immunological Grade: Efforts are underway to establish a standardized "immunological grade" that reflects the strength of an individual patient's antitumor immune response 1

Understanding the complex interactions between the immune system and cancer continues to evolve, driving innovations in immunotherapy and improving outcomes for cancer patients.