Melanoma, a particularly aggressive skin cancer, often evades the immune system due to several immunosuppressive mechanisms. One such mechanism involves Nerve Growth Factor (NGF) and its receptor, Tropomyosin Receptor Kinase A (TrkA). This essay explores how targeting the NGF-TrkA axis can enhance immunotherapy and foster long-lasting protection through memory T cells.
NGF-TrkA: A double-edged sword in melanoma:
- Melanoma cell intrinsic effects: NGF produced by melanoma cells dampens interferon gamma signaling, leading to T and Natural Killer (NK) cell exclusion, creating a “tumor sanctuary.”
- Extrinsic effects on T cells: Upon T cell receptor activation, TrkA expression increases on their surface. Paracrine NGF from melanoma cells then binds to TrkA, suppressing T cell signaling and effector function.
Breaking the immunosuppression:
- Genetic modification: Knocking out TrkA in melanoma cells abrogates these immunosuppressive effects and improves immunotherapy efficacy.
- Larotrectinib, a TrkA inhibitor: This drug shows promise in repurposing for immune sensitization. It effectively blocks NGF-TrkA signaling, restoring T and NK cell function.
Durable memory T cell protection:
- Anti-NGF strategies, including larotrectinib, not only improve initial tumor response but also promote the generation of low-affinity memory T cells. These cells patrol the body, providing long-term protection against cancer recurrence.
- This is important because melanoma often develops resistance to immune checkpoint blockade therapies. Engaging low-affinity T cells overcomes this resistance and leads to more durable responses.