Optimizing the spatial immune landscape of CD103+CD8+ tissue-resident memory T cells in non-small cell lung cancer by neoadjuvant chemotherapy

Background Neoadjuvant chemotherapy (NAC) combined with immunotherapy is increasingly used in non-small cell lung cancer (NSCLC). Tissue-resident memory T (T RM ) cells are the primary subset responding to anti-cancer immunity. However, the immunomodulatory effects of NAC on T RM cells remain unknown. Methods We established two NSCLC cohorts including patients undergoing upfront surgery (US) and NAC followed by surgery. Beyond the unpaired comparison between the US cohort ( n = 122) and NAC cohort ( n = 141) with resection samples, 58 matched pre-NAC biopsy samples were available for paired comparisons. Using multiplex immunofluorescence, we characterized T RM cells (CD103 + CD8 + ) and four heterogeneous T RM subsets, including naive T RM1 (PD-1 − Tim-3 − ), pre-exhausted T RM2 (PD-1 + Tim-3 − ), T RM3 (PD-1 − Tim-3 + ), and terminally exhausted T RM4 (PD-1 + Tim-3 + ). Cell density, cytotoxicity, and two spatial features were defined to evaluate the effect of NAC on T RM subsets. Results The cell densities, infiltration scores, and cancer-cell proximity scores of T RM cells, especially T RM1&2 subsets, were significantly increased after NAC and associated with better prognosis of patients. In Contrast, no significant change was observed in the T RM4 subset, which was associated with poor prognosis. Besides, the cytotoxicity of T RM subsets was unaltered after NAC. Compared with patients without major pathologic response (MPRs), patients with MPR had higher densities of T RM1&2 subsets and higher cancer-cell proximity scores of T RM2&3 subsets. Furthermore, increased density of CD31 + cancer microvessels was positively associated with both T RM and T non−RM cells after NAC. Conclusions NAC may remodel the cell density and spatial distribution of T RM subsets, which is associated with favorable therapeutic effect and prognosis in patients with NSCLC.