Breaking through NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection [scRNA-Seq]

Melanomas are generated from melanocytes, the neural crest derivatives sharing a neuroectodermal origin with the nervous system. In investigating whether immune privilege of the nervous system might be exploited by melanoma, we found that nerve growth factor (NGF) exerts both melanoma cell-intrinsic and -extrinsic immunosuppression. In melanoma cells, autocrine NGF engages TrkA receptor to desensitize IFN-gammasignaling, leading to T and NK cell exclusion. In effector T cells, which upregulate surface TrkA expression upon T cell receptor (TCR) activation, paracrine NGF dampens TCR signaling and effector function. Targeting NGF genetically or pharmacologically with larotrectinib sensitizes melanoma responsiveness to immune checkpoint blockade (ICB) therapy for tumor eradication and induces durable protection by eliciting robust memory of low-affinity T cells. Together, these findings uncover a comprehensive mechanism through which the NGF-TrkA axis suppresses anti-tumor T cell immunity, thus providing a novel mode of action to repurpose larotrectinib for immune sensitization. Moreover, by enlisting low-affinity tumor-specific T cells, anti-NGF reduces acquired resistance to ICB therapy and prevents melanoma recurrence. B16 cells with Ctrl or NGF sgRNA were injected into C57BL/6J mice. Melanoma tissues were harvested on day 10 and CD45+ cells from melanoma tissues were sorted by FACS for single cell RNA-seq. FACS sorting purity was around 85%.