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.