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.