Selectively targeting myeloid-derived suppressor cells through TRAIL receptor 2 to enhance the efficacy of CAR T cell therapy for treatment of breast cancer

• DOI: 10.1136/jitc-2021-003237
• Publication Date: 2021-11-23T17:44:47Z
• Authors: Saisha A Nalawade; Paul Shafer; Pradip Bajgain; Mary K McKenna; Arushana Ali; Lauren Kelly; Jarrett Joubert; Stephen Gottschalk; Norihiro Watanabe; Ann Leen; Robin Parihar; Juan Fernando Ver...; Valentina Hoyos
• Keywords: Myeloid-derived Suppressor Cell

Background Successful targeting of solid tumors such as breast cancer (BC) using chimeric antigen receptor (CAR) T cells has proven challenging, largely attributed to the immunosuppressive tumor microenvironment (TME). Myeloid-derived suppressor (MDSCs) inhibit CAR cell function and persistence within TME. To overcome this challenge, we have developed tumor-associated mucin 1 (MUC1) with a novel costimulatory that targets necrosis factor–related apoptosis-inducing ligand 2 (TR2) expressed on MDSCs. Methods The TR2.41BB was assessed by exposing non-transduced (NT) transduced recombinant TR2, after which nuclear translocation NFκB measured ELISA western blot. cytolytic activity CAR.MUC1/TR2.41BB in 5-hour cytotoxicity assay MUC1+ presence or absence In vivo antitumor MDSC-enriched tumor-bearing mice treated without TR2.41BB. Results Nuclear response TR2 detected only cells. MDSCs diminished cytotoxic potential CAR.MUC1 against BC lines 25%. However, expression induced MDSC apoptosis, thereby restoring lines. resulted an approximately twofold increase growth due enhanced angiogenesis fibroblast accumulation compared alone. Treatment these CAR.MUC1.TR2.41BB led superior killing significant reduction (24.54±8.55 mm 3 ) (469.79±81.46 (434.86±64.25 also demonstrated improved proliferation at site, preventing metastases. We observed similar results CAR.HER2.TR2.41BB HER2+ model. Conclusions Our findings demonstrate coexpress TR2.4-1BB exhibit containing promoting MDSCs, resulting TME remodeling site.