Abstract
Background: The T cell response against different tumors is improved by immunogenic cell death (ICD), indicating a role for ICD in augmenting antitumor immunity elicited by the anti-checkpoint antibody anti-programmed death 1 (anti-PD-1). Methods: The effect of SR-4835 on breast cancer was analyzed by cell proliferation and flow cytometry. Calreticulin translocation and HMGB1 and ATP release were detected by flow cytometry, ELISA and luminescence assay, respectively. Immunogenicity in vitro was analyzed by co-culturing of SR-4835 treated cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of maturation of BMDCs and production of IL-6 in the supernatant were measured. The in vivo antitumor effect was analyzed by syngeneic mouse model followed by flow cytometry for TILs.Results: In the present study, we report a synergistic and durable immune-mediated antitumor response elicited by the combined treatment of SR-4835, a CDK12/13 specific inhibitor, with PD-1 blockade in a murine model of 4T1 breast cancer. The developed combination therapy elicited antitumor activity in immunocompetent mouse tumor models. Furthermore, the SR-4835-treated tumor cells exhibited characteristics of ICD, including the release of high mobility group box 1 (HMGB1) and ATP and the translocation of surface calreticulin (CRT). This activity led to a significant T-cell dependent regression of tumors. The enhanced infiltration of T cells and dendritic cell (DC) activation in the tumors of mice treated with both SR-4835 and anti-PD-1 indicate that this combination treatment promotes an improved immune response and suggests a potential mechanism involving anti-PD-1 and SR-4835 activity that enhances anti-PD-1 effects. Conclusion: The results of the present study demonstrate the potential of CDK12/13 inhibition combined with checkpoint inhibition in breast cancer treatment.
Cyclic dinucleotides modulate human T-cell response through monocyte cell death