ANTI-TUMOUR_IMMUNE_RESPONSE

Anti-Tumour Immune Response

• Role of the Immune System

  • Protects against pathogens and abnormal cells, including cancer.

  • Aims to detect and eliminate malignant cells via various mechanisms.

Strengths of the Anti-Tumour Immune Response

• Two Arms of the Immune System:

  • Innate Immune System: First line of defense includes:

    • Natural killer (NK) cells: Recognize and destroy abnormal cells.

    • Macrophages: Engage in phagocytosis of malignancies.

  • Adaptive Immune System: Tailored response involving:

    • T cells: Highly specific to target cancer cells.

    • B cells: Produce antibodies to tag tumour cells for destruction.

  • Cytotoxic T Lymphocytes (CTLs): Identify and kill tumour cells displaying abnormal antigens.

Weaknesses of the Anti-Tumour Immune Response

• Evading Immune Detection:

  • Cancer cells may downregulate MHC molecules, crucial for presenting tumour antigens to T cells.

  • Production of immunosuppressive molecules:

    • Transforming growth factor-beta (TGF-β)

    • Interleukin-10 (IL-10)

  • Exploitation of immune checkpoint pathways:

    • PD-1/PD-L1 and CTLA-4 pathways inhibit anti-tumour responses.

• Immunosuppressive Tumour Microenvironment (TME):

  • High levels of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs).

  • Presence of inhibitory cytokines hampers effector immune cells function.

• Genetic Instability:

  • Cancer cells exhibit diverse subpopulations, some may not be recognized by the immune system, allowing unchecked tumour growth.

Antibody-based Therapies in Solid Cancer Treatment

• Monoclonal Antibodies (mAbs):

  • Designed to target tumour-associated antigens (TAAs) or immune checkpoints.

  • Examples include:

    • Trastuzumab: Targets HER2 protein, used for HER2-positive breast cancer.

    • Cetuximab: Targets EGFR, used in colorectal and head/neck cancers.

  • Mechanisms:

    • Inhibit tumour growth signals.

    • Recruit immune cells to destroy tumour cells.

    • Induce apoptosis.

• Checkpoint Inhibitors:

  • Block immune checkpoint proteins (e.g., PD-1, PD-L1, CTLA-4).

  • Restore T cells' ability to attack cancer.

  • Examples include:

    • Pembrolizumab/Nivolumab: Target PD-1.

    • Ipilimumab: Targets CTLA-4.

  • Notable successes in treating melanoma, non-small cell lung cancer, and renal cell carcinoma.

Limitations of Antibody-based Therapies

• Resistance can develop over time; not all patients respond.

• Risk of immune-related adverse events (irAEs) due to excessive immune activation.

Future Strategies for Tumour Immunotherapy

• Personalized Cancer Vaccines:

  • Utilize tumour-specific antigens for tailored immune responses.

• Chimeric Antigen Receptor (CAR) T-cell Therapy:

  • Engineers T cells to recognize and eliminate cancer cells.

  • Successful in hematological cancers; research ongoing for solid tumours.

• Combination Therapy Approaches:

  • Integrate checkpoint inhibitors with chemotherapy, radiation, or targeted therapies.

  • Aims to overcome resistance and improve patient outcomes.

• Targeting the Tumour Microenvironment:

  • Strategies to deplete Tregs or MDSCs to enhance immunotherapy effectiveness.

Conclusion

• Anti-tumour immune response has notable strengths but is often hindered by cancer's evasion strategies and immunosuppressive environments.

• Antibody-based therapies, particularly checkpoint inhibitors, have changed cancer treatment paradigms but face resistance and side effects.

• Ongoing research into personalized therapies, CAR T-cell therapy, and combination strategies holds promise for more effective and durable cancer treatments.