Higher proximity of PD-L1+ tumor cells to PD-1+ tissue-resident memory CD8 determines response to neoadjuvant chemoimmunotherapy in non-small cell lung cancer

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Background: Although neoadjuvant chemoimmunotherapy (NCIT) improves outcomes in resectable non-small cell lung cancer (NSCLC), traditional biomarkers like programmed death-ligand 1 (PD-L1) expression are insufficient for accurate patient selection. This study aimed to investigate the spatial interaction between specific T-cell subsets and PD-L1+ tumor cells using multiplex immunofluorescence (mIF), and to evaluate its value in predicting the efficacy of NCIT in NSCLC patients. Methods: We retrospectively recruited 44 patients with stage IIA–IIIB NSCLC who had NCIT at Shandong Cancer Hospital and Institute from January 2021 to June 2023. Pre-treatment specimens were subjected to multicolor immunofluorescence staining (panel 1: CK/PD-L1/PD-1/CD8/CD103/CD4/FOXP3; panel 2: CK/CD8/CD4/α-SMA/CD31/HIF-1α) to quantify PD-L1+ tumor cells and specific target T cells (CD4/conventional CD4/regulatory CD4, CD8/CD8+ TRM/bystander CD8) and to delineate their spatial distribution. The Mann-Whitney U test, receiver operating characteristic (ROC) curves, and logistic regression were employed to examine the correlation between these indicators and treatment response. Spearman correlation analysis assessed their relationship with tumor microvasculature, cancer-associated fibroblasts (CAFs), and hypoxia-inducible factor-1α (HIF-1α). Results: Among the 44 patients, 52.3% showed a response. Compared with non-responders, responders had closer distances between PD-L1+ tumor cells and CD8+ TRM, CD8, bystander CD8, conventional CD4, CD4, and regulatory CD4 prior to treatment, with decreasing area under the curve (AUC) values (0.728, 0.715, 0.680, 0.644, 0.643, 0.612). Further analysis of CD8+ TRM expressing programmed cell death 1 (PD-1) revealed that PD-1+ CD8+ TRM was the best predictor with an AUC of 0.743. Logistic regression analysis indicated that the closer PD-L1+ tumor cells were to CD8+ TRM, the better the treatment response [odds ratio (OR) =10.43, 95% confidence interval (CI): 1.49–73.08, P=0.02], especially for PD-1+ CD8+ TRM (OR =8.83, 95% CI: 1.81–43.13, P=0.007). Additionally, PD-L1+ tumor cell-CD8+ TRM interactions and PD-L1+ tumor cell-PD-1+ CD8+ TRM interactions were significantly positively correlated with HIF-1α+ CD8 (r=0.36 and 0.35, respectively, P<0.001 for both). Conclusions: T cells interacting with PD-L1+ tumor cells may be characterized as PD-1+ CD8+ TRM cells. A closer distance between the two enhances therapeutic efficacy and may be associated with density of hypoxic CD8 cells.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.