| Summary: | Remarkable clinical benefits in several advanced cancers are observed under the treatment of immune checkpoint inhibitor (ICI) agents. However, only a smaller proportion of patients respond to the treatments. Reelin (RELN) is frequently mutated in the cancer genome. In this study, the <i>RELN</i> mutation association with ICI treatment efficacy in melanoma and non-small cell lung cancer (NSCLC) was elucidated. Data from 631 melanoma and 109 NSCLC patients with both ICI treatment data and pre-treatment mutational profiles were collected. In addition, from the Cancer Genome Atlas (TCGA) project, we also obtained both tumors to explore the immunologic features behind <i>RELN</i> mutations. Melanoma patients with <i>RELN</i> mutations exhibited a favorable ICI survival benefit when compared with wild-type patients (HR: 0.66, 95% CI: 0.51–0.87, <i>p</i> = 0.003). A higher response rate was also noticed in <i>RELN</i>-mutated patients (38.9% vs. 28.3%, <i>p</i> = 0.017). The association of <i>RELN</i> mutations with a preferable immunotherapy outcome and response was further confirmed in NSCLC. Further exploration demonstrated that favorable immunocyte infiltration and immune response signaling pathways were found in patients with <i>RELN</i> mutations. In this study, <i>RELN</i> mutations were identified to connect with a better immune microenvironment and an improved ICI efficacy in melanoma and NSCLC, which provides a potential biomarker for immunological feature evaluation and immunotherapeutic outcome prediction at the molecular level.
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