Tumor cell-expressed OX40L enhances the efficacy of PD-1 axis blockade in non-small cell lung cancer.

BACKGROUND

Immune checkpoint inhibitors have transformed non-small cell lung cancer (NSCLC) treatment. Understanding the tumor-immune interactions that dictate sensitivity to PD-1 blockade is essential for improving outcomes and optimizing immunotherapy personalization.

METHODS

We performed compartment-specific (tumor/immune) spatial proteomic profiling (GeoMx) on a discovery cohort of 104 patients with advanced, PD-L1-high (tumor proportion score ≥50%) NSCLC treated with first-line pembrolizumab. Identified markers were further assessed using orthogonal methods in two independent early-stage NSCLC cohorts treated with neoadjuvant/perioperative chemo-immunotherapy: (a) NADIM trial (n=36) with bulk RNA-seq and (b) NeoITX_H12O cohort (N=41) with quantitative immunohistochemistry. Potential baseline prognostic value without immunotherapy was evaluated in the TCGA dataset (N=940). Functional validation was assessed using in vitro and in vivo (nude and syngeneic) models.

RESULTS

We identified tumor-cell OX40L, but not immune-cell OX40L, as the single marker significantly associated with prolonged progression-free survival (PFS) and overall survival under single-agent pembrolizumab in patients with PD-L1-high tumors. Spatially resolved analysis linked tumor-intrinsic OX40L to an active immune microenvironment with increased antigen presentation. In both neoadjuvant/perioperative cohorts, high OX40L levels in residual tumors from patients with non-pathological complete response were associated with superior PFS. Conversely, no significant association with survival was observed in the immunotherapy-naïve TCGA cohort. Functional studies confirmed that OX40L-expressing NSCLC cells directly co-stimulate T cells in vitro and significantly enhance anti-PD-1 efficacy in vivo (p=0.0005), without affecting intrinsic tumor growth.

CONCLUSIONS

OX40L expressed by tumor cells contributes to an enhanced efficacy of PD-1 blockade in patients with NSCLC. These findings may open new therapeutic avenues and potentially contribute to improving immunotherapy personalization in this disease.