Dynamic T‐Cell Reprogramming Modulates the Treatment Outcome of Neoadjuvant Immunochemotherapy in Non‐Small‐Cell Lung Cancer

ABSTRACT Although immunochemotherapy sheds light on neoadjuvant strategies, about two‐thirds of patients still respond poorly to perioperative chemoimmunotherapy. Hence, it is crucial to investigate the underlying response mechanism to improve the prognosis of these patients. In this study, we utilized paired pre‐ and post‐neoadjuvant immunochemotherapy samples from non‐small‐cell lung cancer (NSCLC) patients with single‐cell RNA and T‐cell receptor (TCR) sequencing to characterize the dynamic changes of T cells in tumor microenvironment. Within nine enrolled patients with distinct pathological assessments, we identified bi‐directional mechanisms associated with their pathological responsiveness. One is mediated by a batch of CD8 + T‐cell subsets such as effector memory T cells (Tem), effector T cells (Teff), tissue‐resident memory T cells (Trm), and exhausted T cells (Tex), exhibiting higher TCR clonality and diversity in responders. CD8 + Tem cells with both novel and pre‐existing TCR clonal expansion patterns particularly contributed to improved pathological responses. The other mechanism is through inhibitory Tregs, which showed more novel clonal expansion and enhanced functional profiles in nonresponsive tumors. In conclusion, our findings proposed the bidirectional characteristics of T‐cell dynamics for in‐depth interpretation of responding mechanisms to neoadjuvant immunochemotherapy of NSCLC.