Carmen Fernández-Luna, Javier Baena, Antonio Calles, Mónica Antoñanzas-Basa, Yolanda Lage Alfranca, Xabier Mielgo, Maria Sereno, Raquel Cervera, Luis Cabezon-Gutierrez, Ana López, Judit Rubio, Esther Conde, Fernando Lopez-Rios, Luis Alvarez-Vallina, Karmele Valencia, Luis M Montuenga, Gorka Ruiz De Garibay, Magdalena Molero, Vera Adradas, Daniel Curto-Aguilera, Melina Peressini, Esther Carrera-Elvira, Daniel Ballesteros, Adrián Portillo-Fernández, Teresa Lopez-Cárdenas, Cristina Serrano-Gómez, Helena Bote, Javier Torres-Jiménez, Alberto Cruz-Bermúdez, Mariano Provencio, Luis Paz-Ares, Estela Sánchez-Herrero, Jon Zugazagoitia
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.
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.