A chemical conjugation ofJQ-1 and aTLR7agonist induces tumoricidal effects in a murine model of melanoma via enhanced immunomodulation

In recent years, inhibitors of the BET bromodomain proteins, such as BRD4 inhibitors, have demonstrated robust antitumor activity. JQ-1, a representative small molecular BRD4 inhibitor, is also effective to block PD-1/PD-L1 signaling by significantly decreasing the PD-L1 expression on tumor cells. However, toxicity of BRD4 inhibitors on lymphoid and hematopoietic tissues limits their clinical usage. In this research, we designed and studied an immunogenic BRD4 inhibitor, SZU-119, by coupling JQ-1 with a TLR7 agonist, SZU-101. In vitro, SZU-119 stimulated the production of cytokines in mouse BMDCs and spleen lymphocytes, and inhibited the expression of PD-L1 in mouse B16 tumor cells. In vivo, SZU-119 suppressed the B16 tumor growth at both injected and uninjected sites, and prolonged the survival time of mice. SZU-119 elevated the number of total CD8(+)and IFN-gamma(+)CD8(+)T cells in spleens, with greater CTL cytotoxicity to B16 tumor cells. It was also observed that the infiltration of CD8(+)T cells was increased in tumors at both local and distant sites, and the PD-L1 expression was decreased in tumor cells at the primary site. In conclusion, we have demonstrated that SZU-119 activated the innate immune cells, kept efficacy of PD-L1 blockade and abrogated immune toxicity, showing more potent antitumor effects than the simple mixture of SZU-101 and JQ-1 in a mouse melanoma model. Our work provides new insights for the development of anti-melanoma drugs that concurrently target innate and adaptive immunity.

Automated summary

The immunogenic BRD4 inhibitor SZU-119 designed in this study demonstrated potent antitumor activity, suppressing tumor growth, prolonging survival time of mice, promoting cytokine production and immune cell activation, and enhancing CTL cytotoxicity in a mouse melanoma model. This work provides new insights for the development of anti-melanoma drugs targeting both innate and adaptive immunity.