Pancreatic cancer organoids recapitulate chemotherapy response and identify a potent cytotoxic T cell population

Abstract Purpose: Unsatisfactory outcomes in pancreatic ductal adenocarcinoma (PDAC) highlight the need to identify precision-based treatment modalities. We aimed to utilize patient-derived organoids (PDOs) to predict the most effective individual components of potential combination therapies. Experimental Design: Autologous αβ and γδ-enriched tumor infiltrating lymphocyte (TIL) and PDO cultures were established from resected PDAC tissue. PDOs were characterized by immunostaining, targeted next-generation sequencing, and drug screening with standard-of-care multidrug chemotherapeutic regimens. Expanded TIL cultures were profiled through flow cytometry, sequencing, and potency against autologous PDOs. Results: PDO cultures were established with an 80% success rate. In addition to faithfully recapitulating molecular and histological features of the parental tumor, PDOs were sufficiently expanded for pharmacotyping within a clinically relevant timeframe of 36 days. Notably, PDO chemotherapeutic sensitivity profiles correlated with patient serum CA 19-9 dynamics and recurrence free survival. Furthermore, expanded γδ-enriched TIL supported the activation of αβ TCR+ cells and demonstrated more potent functionality in response to autologous PDO targets. Importantly, infiltration of γδ T cells within pancreatic tumor tissue was associated with improved overall survival. Conclusions: We confirm the feasibility of generating PDOs within a clinically relevant timeframe and provide evidence of their utility for advancing therapeutic success in PDAC.