Tumor immunology

Tumor Antigens - Spotting the Enemy

• Tumor-Specific Antigens (TSAs):

  • Found exclusively on tumor cells.
  • Primarily neoantigens resulting from mutations; these are highly immunogenic.

• Tumor-Associated Antigens (TAAs):

  • Also on normal cells, but expression is altered.
  • Oncofetal antigens: AFP, CEA.
  • Differentiation antigens: CD20 on B-cells.
  • Overexpressed proteins: HER2 in breast cancer.
  • Viral antigens: HPV E6/E7 in cervical cancer.

⭐ Neoantigens, arising from somatic mutations, are highly immunogenic and are the principal targets for effective T-cell-mediated tumor destruction.

Immune Surveillance - The Cancer Patrol

The immune system's intrinsic ability to recognize and eliminate cancer cells. This process, primarily cell-mediated, involves a coordinated attack on tumor cells.

• Key Cellular Players:

  • Cytotoxic T-Lymphocytes (CTLs): The primary assassins. Recognize tumor antigens on MHC-I and induce apoptosis.
  • Natural Killer (NK) Cells: Innate defenders. Target cells with ↓MHC-I expression (a common tumor evasion tactic).
  • Macrophages: Dual role. M1 (pro-inflammatory) are tumoricidal; M2 (pro-tumor) can promote growth.
  • Dendritic Cells (DCs): The messengers. Capture tumor antigens and present them to T-cells (cross-presentation).

• Key Cytokines: IFN-γ, TNF-α, IL-12 orchestrate the anti-tumor response.

⭐ The 'cancer-immunity cycle' describes the series of steps required for an effective anti-tumor immune response, from antigen release to cancer cell killing.

Immune Evasion - Cancer's Cloaking Device

• Antigenic Modulation: Cancer cells lose or mask tumor-specific antigens (TSAs), effectively becoming "invisible" to patrolling T cells.
• MHC Downregulation: ↓ MHC-I expression on the tumor cell surface prevents cytotoxic T lymphocytes (CTLs) from recognizing and killing them.
• Immune Checkpoint Upregulation: ↑ expression of proteins like PD-L1 and CTLA-4, which act as "brakes" to deactivate T cells.
• Immunosuppressive Environment: Secretion of cytokines like TGF-β and IL-10 to inhibit T-cell and NK-cell function.
• Recruitment of Suppressor Cells: Induction of regulatory T cells (Tregs) and Myeloid-Derived Suppressor Cells (MDSCs) to actively turn off the anti-tumor response.

⭐ Tumors frequently upregulate PD-L1 expression, which binds to PD-1 on activated T cells, inducing T-cell 'exhaustion' and allowing the tumor to escape immune destruction.

📌 Mnemonic: "HIDE"

• Hide Antigens
• Inhibit T-cells (PD-L1, CTLA-4)
• Downregulate MHC
• Emit suppressive signals (TGF-β, IL-10)

Immunotherapy - Re-Arming the Guards

Modern therapies leveraging the body's immune system to fight cancer by overcoming tumor defense mechanisms.

• Checkpoint Inhibitors: Release the "brakes" on T-cells, enabling them to attack cancer.

  • Anti-PD-1/PD-L1 (e.g., Pembrolizumab): Blocks T-cell exhaustion signals.
  • Anti-CTLA-4 (e.g., Ipilimumab): Prevents early T-cell inactivation.

  ⭐ Immune-related adverse events (irAEs) are a unique and critical side effect profile of checkpoint inhibitors, caused by generalized immune activation against normal tissues.

• Adoptive Cell Transfer (ACT): Harvest, modify, and re-infuse a patient's T-cells.

  • CAR-T Cells: T-cells engineered with Chimeric Antigen Receptors (e.g., anti-CD19).
  • Tumor-Infiltrating Lymphocytes (TIL): Expansion of naturally anti-tumor T-cells.

• Monoclonal Antibodies: Target specific tumor antigens for destruction.

  • Rituximab: anti-CD20 (B-cell lymphomas).
  • Trastuzumab: anti-HER2 (breast cancer).

• Cancer Vaccines: Prophylactic (HPV) or therapeutic (Sipuleucel-T).
• Cytokine Therapy: Broad immune stimulation (e.g., IL-2, IFN-α).

High‑Yield Points - ⚡ Biggest Takeaways

• Cytotoxic T-lymphocytes (CTLs) are the primary mediators of anti-tumor immunity, recognizing tumor antigens via MHC-I.
• Tumors evade immunity by downregulating MHC-I, expressing PD-L1 to induce T-cell exhaustion, and secreting immunosuppressive cytokines like TGF-β.
• Checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4) block negative signals to T-cells, restoring their anti-cancer activity.
• Natural Killer (NK) cells provide innate immunity by killing cells that have lost MHC-I expression.
• CAR-T cell therapy engineers a patient's T-cells to target tumor antigens, effective in hematologic cancers.