Novel co-culture strategies of tumor organoids with autologous T-cells reveal clinically relevant combinations of immune-checkpoint and targeted therapies

Author:

Podaza EnriqueORCID,Capuano Jared,Assaad Majd Al,Kuo Hui-HsuanORCID,Markowitz GeoffreyORCID,Irizarry Adriana,Ravichandran HiranmayiORCID,Ackermann SarahORCID,Kane Troy,Manohar Jyothi,Sigouros Michael,Moyer Jenna,Bhinder BhavneetORCID,Chandra Pooja,Malbari Murtaza,Boehnke Karsten,Mosquera Juan MiguelORCID,Mittal VivekORCID,Sboner AndreaORCID,Gokozan HamzaORCID,Altorki NasserORCID,Elemento OlivierORCID,Martin M. LauraORCID

Abstract

AbstractPatient derived tumor organoids (PDTOs) have become relevant pre-clinical models for therapeutic modelling since they highly recapitulate patients’ response to treatment. Nevertheless, their value for immunotherapy modelling has not been fully explored. We developed a tumor processing protocol that enable the establishment of PDTOs and tumor infiltrating lymphocytes (TILs) isolation. By the optimization of functional assays, we compared the T-cells effector functions of matching PBMCs and TILs, demonstrating that PBMCs after co-culture and TILs after initial expansion display similar responses. In addition, the evaluation of cytokine production by fluorospot in combination with an image-based killing assay enable the screening of different immune-checkpoint inhibitors as well as its combination with target inhibitors. Our proof-of-concept functional assays showed the potential and versatility of PDTOs and T-cells co-culture systems for immunotherapy screening. The optimization of scalable functional assays downstream co-culture represents a significant step forward to increase the value of PDTOs as pre-clinical models for immunotherapeutic screens.

Publisher

Cold Spring Harbor Laboratory

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