Targeting NTRK1 Enhances Immune Checkpoint Inhibitor Efficacy in NTRK1 Wild-type Non-Small Cell Lung Cancer

Abstract Treatment of non-small cell lung cancer (NSCLC) has drastically changed in recent years owing to the robust anti-cancer effects of immune-checkpoint inhibitors (ICI). However, only 20% of NSCLC patients benefit from ICIs, highlighting the need to uncover the mechanisms mediating resistance. By analyzing the overall survival (OS) and mutational profiles of 424 NSCLC patients who received ICI treatments between 2015 and 2021, we determined that patients carrying a loss of function mutation in neurotrophic tyrosine kinase receptor 1 (NTRK1) had a prolonged OS compared to patients with wild-type NTRK1. Notably, suppression of the NTRK1 pathway by knockdown or Entrectinib treatment significantly enhanced ICI efficacy in mouse NSCLC models. Comprehensive T cell population analyses demonstrated that stem-like CD4+ T cells and effector CD4+ and CD8+ T cells were highly enriched in anti-PD-1 treated mice bearing tumors with decreased NTRK1 signaling. RNA sequencing revealed that suppression of NTRK1 signaling in tumor cells increased complement C3 expression, which enhanced the recruitment of T cells and myeloid cells and stimulated M1-like macrophage polarization in the tumor. Together, this study demonstrates a role for NTRK1 signaling in regulating crosstalk between tumor cells and immune cells in the tumor microenvironment and provides a potential therapeutic approach to overcomes immunotherapy resistance in NTRK1 wild-type NSCLC patients.