Middle-high altitude residence as a predictor of improved immune checkpoint inhibitor outcomes in advanced NSCLC: A multicenter cohort study.

Abstract

e20597 Background: Immune checkpoint inhibitors (ICIs) have transformed treatment for advanced non-small cell lung cancer (NSCLC), but clinical effectiveness remains variable. Altitude may modulate host immunity and treatment responses. This study investigated the association between residential altitude and outcomes, and explored potential mechanism. Methods: This is a retrospective cohort study across 11 medical centers in China. Patients with advanced NSCLC receiving ICIs were classified by residential altitude: low-altitude ( < 1000m), middle-altitude (1000-2000m) and high-altitude ( > 2000m). Endpoints included progression-free survival (PFS) and overall survival (OS). Landmark and restricted mean survival time (RMST) analyses were employed due to violation of proportional hazards assumptions. Propensity score matching (PSM) and Cox regression addressed confounding. Tumor immune profiles were characterized by RNA sequencing and multiplex immunohistochemistry. Results: A total of 1793 patients were included: low-altitude (n = 1024), middle-altitude (n = 342), and high-altitude (n = 427). Median PFS was 11.2 months in low-altitude groups, 14.7 months in middle-altitude and 13.4 months in high-altitude. 2-years landmark analyses demonstrated improved PFS in both middle-altitude (HR = 0.78, 95%CI 0.65-0.93, P = 0.0058) and high-altitude (HR = 0.77, 95%CI 0.65-0.91, P = 0.0018) groups versus the low-altitude group, with no difference between the former two. Thus, we pooled these into a single M-H (middle-high) altitude group (n = 769). In PSM cohort, RMST analysis showed sustained PFS benefit with M-H altitude at 1 year (0.79 months, P = 0.0002), 2 years (1.70 months, P = 0.0007), and 3 years (1.88 months, P = 0.0171). Multivariable Cox regression during the first 2 years confirmed lower progression risk with M-H altitude (HR 0.78, 95%CI 0.68-0.89, P = 0.0003). OS benefit was significant at 1-2 years but attenuated by year 3. Further analyses demonstrated PFS and OS benefit with M-H altitude in most subgroups. RNA sequencing (n = 124) revealed higher effector cell and lower suppressor cell immunophenoscores with M-H altitude. Immunohistochemistry (n = 172) demonstrated increased tissue-resident memory CD8 + T cell infiltration associated with improved outcomes. Conclusions: M-H altitude residence is independently associated with improved clinical outcomes in advanced NSCLC patients receiving ICIs. This is supported by enhanced effector immune signatures and tissue-resident memory CD8 + T cell infiltration in tumors from M-H-altitude residents.