<p>Transcriptional upregulation of pro-apoptotic mediators and IFN-I in B16 and Panc02 cells, and apoptosis induction in Panc02 cells after co-culture with CAR T cells in the presence of 3pRNA-conditioned culture medium</p>
Funding
Wilhelm Sander-Stiftung (Wilhelm Sander Foundation)
Melanoma Research Alliance (MRA)
José Carreras Leukämie-Stiftung (DJCLS)
European Hematology Association (EHA)
Deutsche Forschungsgemeinschaft (DFG)
Bavarian Cancer Research Center (BZKF)
Elitenetzwerk Bayern (ENB)
Horizon 2020 Framework Programme (H2020)
Else Kröner-Fresenius-Stiftung (EKFS)
Deutsche Krebshilfe (German Cancer Aid)
Jung-Stiftung für Wissenschaft und Forschung (Jung-Stiftung)
Bundesministerium für Bildung und Forschung (BMBF)
Bayerisches Staatsministerium für Wirtschaft und Medien, Energie und Technologie (Bavarian Ministry of Economic Affairs and Media, Energy and Technology)
European Research Council (ERC)
Fritz-Bender-Stiftung (Fritz Bender Foundation)
Hector Stiftung II (Hector Foundation II)
Bayerische Forschungsstiftung (Bavarian Research Foundation)
Bruno and Helene Jöster Foundation
Monika-Kutzner Foundation
ARTICLE ABSTRACT
Despite the remarkable success of chimeric antigen receptor (CAR) T cells in certain hematologic malignancies, only modest responses have been achieved in solid tumors. Defective cell death pathways have recently been suggested as a tumor-intrinsic form of resistance to CAR T-cell treatment. In this study, we showed that insufficient activity of the innate RNA-sensing receptor system retinoic acid–inducible gene I (RIG-I)/mitochondrial antiviral signaling protein (MAVS) leads to tumor cell–inherent resistance to CAR T-cell attack. Active RIG-I/MAVS signaling in tumor cells primed intrinsic mitochondrial apoptosis pathways and expression of cell death receptors, which funneled into CAR T-cell–triggered cell death. CAR T-cell reliance on tumor-intrinsic RIG-I signaling was observed in various murine and human cancer types, independent of the CAR construct used, and the dependence was most pronounced under conditions with low target antigen expression or low effector/target ratios. RIG-I–induced proapoptotic priming of CAR T-cell susceptibility involved auto-/paracrine type-I IFN signaling loops and could spread to bystander tumor cells. Strong tumor-intrinsic RIG-I/MAVS signaling imprinted an activated cytolytic phenotype on tumor-interacting CAR T cells. Agonist-mediated targeting of the RIG-I pathway in the tumor microenvironment rendered murine melanoma susceptible to CAR T-cell therapy in vivo with enhanced infiltration of active CAR T cells. Together, these data identify insufficient RIG-I/MAVS activity and associated impaired cell death signaling in malignant cells as a resistance mechanism to CAR T cells. Targeting tumor-intrinsic RIG-I is a potential strategy to sensitize solid tumors to CAR T-cell treatment.
Insufficient activity of the RIG-I/MAVS pathway is a tumor intrinsic resistance mechanism to CAR T cells, providing the rationale for targeting RIG-I to optimize CAR T efficacy in patients with solid cancers.
