Pan-cancer analysis reveals that neurotrophin signaling correlates positively with anti-tumor immunity, clinical outcomes, and response to targeted therapies and immunotherapies in cancer

Aims: The crosstalk between cancer cells and nerves plays an important role in tumor biology. However, the correlation between the neurotrophin signaling (NS) and anti-tumor immunity and immunotherapy response in cancer remains unexplored. Materials and methods: We analyzed associations of NS with anti-tumor immune signatures, tumor immunity related molecular and genomic features, and clinical features in 33 TCGA cancer types. We also explored the association between NS and the response to immune checkpoint inhibitors (ICIs) in four cancer cohorts. Key findings: NS scores had significant positive correlations with the enrichment scores of anti-tumor immune signatures, including CD8+ T cells, interferon response, natural killer cells, Toll-like receptor and NOD-like receptor signaling pathways in most cancer types. NS scores were inversely correlated with the scores of DNA damage repair pathways, tumor mutation burden, copy number alterations, intra-tumor heterogeneity, and tumor stemness in diverse cancers. In contrast, NS scores were significantly and positively correlated with the apoptosis pathway's scores in 32 of the 33 cancer types. NS scores were significantly lower in early-stage versus late-stage and in primary versus metastatic tumors in diverse cancers. Higher NS scores were correlated with better survival in pan-cancer and in eight individual cancer types. Moreover, the response rate to ICIs was higher in higher-NS-score than in lower-NS-score tumors in four cancer cohorts. Elevated NS was correlated with increased drug sensitivity for numerous anti-tumor targeted drugs. Significance: NS is a positive biomarker for anti-tumor immune response, prognosis, and the response to targeted and immunotherapeutic drugs in cancer.