Tumor Immunology

Tumor Antigens - Cancer's ID Tags

• Molecules on tumor cells recognized by the immune system (T cells, antibodies).
• Key to immunotherapy & diagnostics.

Types of Tumor Antigens:

• Tumor-Specific Antigens (TSAs):
  • Exclusively on tumor cells.
  • Arise from mutations (e.g., mutated p53, RAS) or viral oncogenes (e.g., HPV E6/E7).
  • Ideal targets for therapy.
• Tumor-Associated Antigens (TAAs):
  • Also on normal cells, but overexpressed or aberrantly expressed on tumors.
  • Examples:
    • Oncofetal antigens: AFP (liver cancer), CEA (colon cancer).
    • Differentiation antigens: PSA (prostate cancer), MART-1 (melanoma).
    • Overexpressed self-proteins: HER2/neu (breast cancer).

⭐ CEA (Carcinoembryonic Antigen) is a classic TAA used primarily for monitoring colorectal cancer recurrence, not for initial diagnosis due to low specificity/sensitivity.

📌 Mnemonic: Tumor Specific = Solely on Tumors; Tumor Associated = Also on normal, but Abnormal on Tumors.

Immune Surveillance - Body's Cancer Cops

• Natural defense: Recognizes & eliminates nascent transformed cells.
• Mediated by both innate & adaptive immunity.
• Key Effector Cells:
  • Innate:
    • Natural Killer (NK) cells: Target cells with ↓MHC-I or stress ligands (e.g., MICA/B). Release perforin, granzymes.
    • M1 Macrophages: Phagocytosis, release TNF-α, NO.
  • Adaptive:
    • Cytotoxic T Lymphocytes (CTLs/CD8+ T cells): Recognize tumor antigens on MHC-I. Induce apoptosis (perforin/granzymes, Fas-FasL).
    • Helper T cells (Th1/CD4+ T cells): Secrete IFN-γ (activates CTLs, Mφ), TNF-α.

⭐ IFN-γ, produced mainly by Th1 cells and NK cells, is pivotal for anti-tumor immunity by activating macrophages and enhancing CTL differentiation and killing.

• Evidence: ↑cancer incidence in immunosuppressed individuals (e.g., AIDS, transplant recipients).

Tumor Evasion - Cancer's Escape Artistry

• ↓ MHC-I Expression:
  • Tumor cells evade CTL recognition.
  • Mutations in TAP, β2-microglobulin.
• Antigen Masking/Shedding:
  • Glycocalyx (sialomucins) hides antigens.
  • Shed antigens neutralize antibodies.
• Immunosuppressive Microenvironment:
  • Secretion: TGF-β, IL-10.
  • Recruitment: Tregs, MDSCs.
  • Checkpoint Ligands:
    • PD-L1 (tumor) binds PD-1 (T-cell) → T-cell exhaustion.
    • CTLA-4 (T-cell) binds B7 ligands (tumor/APCs) → ↓ T-cell activation.
• Induce T-cell Apoptosis:
  • Tumor FasL binds Fas on T-cells → apoptosis.
• Lack of Co-stimulation:
  • Absent B7 (CD80/CD86) on tumor cells → T-cell anergy.
• Antigenic Variation:
  • Immune selection of antigen-negative variants.

⭐ PD-L1 expression on tumor cells binds PD-1 on T-cells, causing T-cell exhaustion. This is a key immune escape targeted by checkpoint inhibitors (e.g., Pembrolizumab).

Cancer Immunotherapy - Boosting The Defense

• Principle: Augmenting patient's immune system to target and destroy cancer cells.
• Key Strategies:
  • Immune Checkpoint Inhibitors (ICIs):
    • Block T-cell inhibitory signals (PD-1/PD-L1, CTLA-4).
    • E.g., Pembrolizumab (anti-PD-1), Ipilimumab (anti-CTLA-4).
    • Unleashes T-cell anti-tumor response.
  • Adoptive Cell Therapy (ACT):
    • CAR T-cells: T-cells engineered with Chimeric Antigen Receptors (e.g., anti-CD19 for B-cell malignancies).
    • TILs: Ex vivo expanded Tumor-Infiltrating Lymphocytes.
  • Cancer Vaccines: E.g., Sipuleucel-T (prostate cancer).
  • Oncolytic Viruses: E.g., T-VEC (melanoma).
  • Cytokines: Non-specific immunostimulants (IL-2, IFN-α).

⭐ Immune Checkpoint Inhibitors (ICIs) targeting PD-1/PD-L1 (e.g., Pembrolizumab) have revolutionized treatment for melanoma, NSCLC, and renal cell carcinoma.

High‑Yield Points - ⚡ Biggest Takeaways

• Tumor Antigens: Include Tumor-Specific Antigens (TSAs) and Tumor-Associated Antigens (TAAs).
• Immune Surveillance: Primarily mediated by Cytotoxic T Lymphocytes (CTLs) and NK cells.
• Tumor Evasion Strategies: Include ↓MHC-I expression, PD-L1 upregulation, and immunosuppressive cytokines.
• Immune Checkpoint Blockade: Anti-PD-1/PD-L1 and Anti-CTLA-4 therapies reinvigorate T-cell responses.
• Adoptive Cell Therapy: CAR T-cells are engineered to recognize and kill cancer cells.
• Chronic Inflammation: Can promote tumorigenesis by creating a favorable microenvironment_