Comprehensive analysis of T cell receptor repertoire in patients with<i> KRAS</i> mutant non-small cell lung cancer

Abstract

Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes in non-small cell lung cancer (NSCLC). The administration of immunotherapy has demonstrated significant efficacy in prolonging the overall survival of patients with KRAS mutation in recent years. However, the efficacy of immunotherapy in KRAS mutant NSCLC is variable. Analysis of T cell receptor (TCR) repertoire may contribute to a better understanding of the mechanisms behind such differential outcomes. Methods: A total of 47 patients with KRAS mutant NSCLC were enrolled in this study. Deep sequencing of the TCR β chain complementarity-determining regions in tumor tissue and paired peripheral blood specimens was conducted. Comprehensive analysis of TCR repertoire metrics was performed with different KRAS mutation subtypes and concomitant mutations. Moreover, the associations between TCR repertoire metrics and tumor mutation burden (TMB), as well as programmed death-ligand 1 were explored, respectively. Results: TCR repertoire metrics, including Shannon index, Clonality, and Morisita index (MOI), showed no significant differences among different KRAS mutation subtypes. The similar results were observed between patients with tumor protein p53 (TP53) mutation and those with wild-type TP53. In contrast, although no significant differences were found in Shannon index and Clonality, patients with KRAS/serine/threonine kinase 11 (STK11) comutation showed a significantly higher MOI compared to their STK11 wild-type counterparts (P=0.012). In addition, TCR repertoire metrics were neither associated with TMB nor programmed death-ligand 1 expression in KRAS mutant NSCLC. Conclusions: This retrospective study comprehensively described the TCR repertoire in KRAS mutant NSCLC. A higher MOI represented more overlap of the TCR repertoire between tumor tissue and paired peripheral blood, indicating distinctive immunological features in NSCLC with KRAS/STK11 comutation.