Association of MUC19 Mutation With Clinical Benefits of Anti-PD-1 Inhibitors in Non-small Cell Lung Cancer

Abstract

Although anti-PD-1 inhibitors exhibit impressive clinical results in non-small cell lung cancer (NSCLC) cases, a substantial percentage of patients do not respond to this treatment. Moreover, the current recommended biomarkers are not perfect. Therefore, it is essential to discover novel molecular determinants of responses to anti-PD-1 inhibitors. We performed Whole Exome Sequencing (WES) in a cohort of 33 Chinese NSCLC patients. Patients were classified into the durable clinical benefit (DCB) and no durable benefit (NDB) groups. Infiltrating CD8⁺ cells in the tumor microenvironment (TME) were investigated by immunohistochemistry. We also used public datasets to validate our results. In our cohort, good clinical responses to anti-PD-1 inhibitors were more pronounced in younger patients with lower Eastern Cooperative Oncology Group (ECOG) scores and only extra-pulmonary metastasis. More importantly, we identified a novel <i>MUC19</i> mutation, which was significantly enriched in DCB patients (<i>P</i> = 0.015), and <i>MUC19-</i>mutated patients had a longer progression-free survival (PFS) (hazard ratio = 0.3, 95% CI 0.1-0.9; <i>P</i> = 0.026). Immunohistochemistry results indicated that the <i>MUC19</i> mutation was associated with increased infiltration by CD8⁺ T cells in the TME (<i>P</i> = 0.0313). When combining <i>MUC19</i> mutation with ECOG scores and intra-pulmonary metastasis status, patients with more positive predictors had longer PFS (<i>P</i> = 0.003). Furthermore, <i>MUC19</i> mutation was involved in immune responses and associated with a longer PFS in the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort. Collectively, we identified that <i>MUC19</i> mutations were involved in immune responses, and NSCLC tumors harboring mutated <i>MUC19</i> exhibited good responses to anti-PD-1 inhibitors.