Chap, B. S.; Santoro, T.; Kosti, P.; Barras, D.; Fahr, N.; Desbuisson, M.; Benedetti, F.; Minasyan, A.; Andreoli, A.; Ghisoni, E.; De Carlo, F.; Benkortbi, K.; Salivaris, A.; Achtari, C.; Hastir, D.; Berezowska, S.; Abdelhamid, K.; Sempoux, C.; Perentes, J. Y.; Mathevet, P.; Garcia, J. C.; Coukos, G.; Dunn, S. M.; Lanitis, E.; Dangaj Laniti, D.

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 E2 (PGE2) inversely correlated with BiTE-induced T cell activation, identifying the COX/PGE2 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.