Tumor Immunity

Tumor Antigens - Cancer's ID Tags

• Molecules on tumor cells recognized by T-lymphocytes, enabling immune surveillance.
• Key Classes:
  • Tumor-Specific Antigens (TSAs):
    • Unique to tumor cells; not on normal cells.
    • E.g., Products of mutated genes (neoantigens like mutated p53, RAS), viral antigens (HPV E6/E7).
  • Tumor-Associated Antigens (TAAs):
    • Present on normal cells, but overexpressed or aberrantly expressed on tumor cells.
    • E.g., Oncofetal (AFP, CEA), Differentiation (CD20, PSA), Overexpressed (HER2/neu, MAGE).

⭐ Neoantigens, derived from somatic mutations, are highly specific to tumors and are primary targets for successful T-cell based immunotherapies like checkpoint inhibitors and CAR-T cells. They correlate with better prognosis and response to immunotherapy in many cancers (e.g., melanoma, lung cancer).

Anti-Tumor Immunity - Body's Cancer Cops

• Body's defense against cancer, involving both innate & adaptive immunity.
• Key Players:
  • Cytotoxic T Lymphocytes (CTLs/CD8+): Principal mediators. Recognize tumor antigens on MHC-I. Kill via perforin/granzymes & Fas-FasL.
  • Natural Killer (NK) Cells: Innate. Kill cells with ↓MHC-I or stress signals. Antibody-Dependent Cell-mediated Cytotoxicity (ADCC).
  • Macrophages (M1 type): Phagocytose, release TNF-α, NO, ROS. Activated by IFN-γ.
  • Helper T Cells (CD4+ Th1): Secrete IFN-γ (activates CTLs, M1; ↑MHC-I/II), IL-2 (T-cell growth).
  • Antibodies: Opsonization, complement activation, ADCC.
• Key Cytokines: IFN-γ, TNF-α, IL-2, IL-12.

⭐ Cytotoxic T Lymphocytes (CTLs) are the most important immune cells for killing tumor cells, recognizing tumor antigens presented on MHC Class I molecules.

Immune Evasion - Tumors' Stealth Mode

Tumors develop sophisticated mechanisms to evade immune destruction, ensuring their survival. 📌 Mnemonic: HIDE

• Hide Antigens:
  • ↓ MHC-I expression: Evades CD8+ T-cell recognition.
  • Antigen loss or masking of tumor antigens.
• Induce Tolerance/Inhibition:
  • ↑ PD-L1: Binds T-cell PD-1, causing exhaustion/anergy.
  • Recruit Tregs to suppress anti-tumor responses.
• Deactivate Immune Cells:
  • Secrete immunosuppressive cytokines (TGF-β, IL-10).
  • Induction of Myeloid-Derived Suppressor Cells (MDSCs).
• Evade Apoptosis:
  • Resist CTL/NK killing (e.g., ↓Fas, anti-apoptotic proteins).

⭐ Upregulation of PD-L1 by tumor cells, leading to T-cell inactivation via PD-1, is a critical immune escape mechanism. Checkpoint inhibitors targeting PD-1/PD-L1 have revolutionized cancer therapy.

Cancer Immunotherapy - Supercharging Defenses

• Immune Checkpoint Inhibitors (ICIs): Block T-cell inhibitory signals.
  • Anti-CTLA-4: Ipilimumab.
  • Anti-PD-1: Nivolumab, Pembrolizumab.
  • Anti-PD-L1: Atezolizumab, Durvalumab.
  • AEs: Immune-related adverse events (irAEs) e.g., colitis, dermatitis, hepatitis, endocrinopathies.
• Adoptive Cell Therapy (ACT): Infuse modified immune cells.
  • CAR T-cells: T-cells genetically engineered with Chimeric Antigen Receptors (e.g., anti-CD19 for B-cell ALL/lymphoma).
    • AEs: Cytokine Release Syndrome (CRS), ICANS (neurotoxicity).
  • TILs: Tumor-Infiltrating Lymphocytes expanded & reinfused.
• Cancer Vaccines: Stimulate anti-tumor immunity.
  • Therapeutic: Sipuleucel-T (prostate Ca).
• Oncolytic Viruses: Viruses lyse cancer cells, trigger immunity.
  • Example: T-VEC (melanoma).
• Cytokine Therapy: Enhance immune function.
  • IL-2 (RCC, melanoma); IFN-α.

⭐ PD-1/PD-L1 inhibitors (e.g., Pembrolizumab, Nivolumab) have transformed cancer treatment by blocking tumor immune evasion.

High‑Yield Points - ⚡ Biggest Takeaways

• Tumor antigens (TSAs, TAAs) are key targets for immune recognition and attack.
• CD8+ CTLs are the most important effector cells in anti-tumor immunity.
• NK cells kill tumor cells, especially those with low MHC-I expression.
• Tumors evade immunity by antigen loss, MHC-I downregulation, and PD-L1 expression.
• Checkpoint inhibitors (anti-PD-1/PD-L1, anti-CTLA-4) boost T-cell mediated tumor destruction.
• CAR T-cell therapy engineers patient T-cells to effectively target and kill cancer.