PT  - JOURNAL ARTICLE
AU  - Devanjali Dutta
AU  - François Rivest
AU  - L. Francisco Lorenzo-Martín
AU  - Nicolas Broguiere
AU  - Lucie Tillard
AU  - Simone Ragusa
AU  - Nathalie Brandenberg
AU  - Sylke Höhnel
AU  - Damien Saugy
AU  - Sylvie Rusakiewicz
AU  - Krisztian Homicsko
AU  - George Coukos
AU  - Matthias P. Lutolf
TI  - Probing the killing potency of tumor-infiltrating lymphocytes on microarrayed autologous tumoroids
AID  - 10.1101/2021.03.30.437679
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.30.437679
4099  - http://biorxiv.org/content/early/2021/03/31/2021.03.30.437679.short
4100  - http://biorxiv.org/content/early/2021/03/31/2021.03.30.437679.full
AB  - Immunotherapy has shown promise as an approach to fight cancer by harnessing the immune system. However, due to the lack of biomarkers to guide treatment regimens and predict response rates, there is an unmet need for more robust ex vivo and in vitro systems that recapitulate patient-specific tumor biology and enable response prediction for immune therapies in an autologous setting. To address this issue, we developed a high-content screening-compatible assay based on microcavity arrays to study tumor-infiltrating lymphocyte (TIL) functionality on 3D tumoroid models. We validated our system using the pmel-1 activated T cell mouse model to assess both cancer immunogenicity and T cell functionality. To demonstrate the translational potential of the platform, we used it to evaluate the response of patient-derived TILs to autologous human colorectal cancer (CRC) tumoroids. Using a combination of imaging and flow cytometry, we determined several features of the antitumor activity of TILs, including the extent of tumoroid killing and secretion of cytokines. We then used the approach to identify responders to immunotherapy, such as the immune checkpoint blockade (ICB) agent Nivolumab (PD-1 inhibitor) and Ipilimumab (CTLA-4 inhibitor). Our system allows not only the identification of immunogenic tumors, but also the testing of patients for response to immunomodulators, enabling personalized immuno-oncology.Competing Interest StatementThe EPFL has filed for patent protection on the hydrogel microcavity array device and organoid array technology described herein, and M.P.L., N.B. and S.H. are named as inventors on those patent applications.