Actionable spatial prostanoid barriers constrain BiTE-driven adoptive T cell immunity in intact human tumors
Year: 2026
Type: preprint
Abstract: Adoptive cell therapy (ACT) in solid tumors is limited by tumor microenvironment (TME)-imposed resistance mechanisms that are inadequately addressed by conventional systems. We developed tissue-preserving patient-derived explants (PDEs) from lung and ovarian cancer to interrogate redirected T cell immunity in intact human tissue. Using mesothelin-targeting bispecific T cell engager (BiTE ® , Amgen trademark)-secreting T cells, we observed antigen-dependent but heterogeneous responses across lesions. An integrated ex vivo response score stratified responder and non-responder TMEs, revealing that resistance associates with reduced antigen density, stromal dominance, and limited myeloid licensing rather than baseline lymphocyte abundance. Elevated prostaglandin E 2 (PGE 2 ) inversely correlated with BiTE-induced T cell activation, identifying the COX/PGE 2 axis as a tissue-imposed constraint. COX inhibition amplified interferon-driven immune programs enhanced intratumoral CD8⁺ infiltration, and increased tumor-restricted apoptosis. Spatial transcriptomics localized these effects to tumor-proximal immune hubs in responders, whereas non-responders remained stromally insulated. These findings position PDEs as human-based new approach methodologies enabling combinatorial ACT pharmacodynamics and stratification. Statement of significance Patient-derived explants provide a human-based new approach methodology to interrogate adoptive immunotherapy pharmacodynamics within intact tumor microenvironments in NSCLC and HGSOC. We uncover a COX/PGE 2 -mediated tissue ceiling that limits BiTE-driven T cell function and demonstrate that COX inhibition reactivates tumor-proximal immune hubs to enhance intratumoral CD8 infiltration and tumor-restricted apoptosis, informing patient stratification and rational combinations.
Authors: Bovannak S. Chap, Tania Santoro, Paris Kosti, David Barras, Noémie Fahr, Mathieu Desbuisson, Fabrizio Benedetti, Aspram Minasyan, Asia Andreoli, Eleonora Ghisoni, Flavia De Carlo, Khadidja Benkortbi, Apostolos Sarivalasis, Chahin Achtari, Delfyne Hastir, Sabina Berezowska, Karim Abdelhamid, Christine Sempoux, Jean Yannis Perentes, Patrice Mathevet, Jose Ramon Conejo-Garcia, George Coukos, Steven M. Dunn, Evripidis Lanitis, Denarda Dangaj Laniti
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Fondation ISREC
OpenAlex ID: W7143527469