BET bromodomain inhibition synergizes with immune checkpoint blockade to facilitate anti-tumor response in a murine model of non-small cell lung cancer harboring activating KRAS mutation

Abstract

Abstract KRAS mutations accounts for about 30% of human non-small cell lung cancer (NSCLC) and represent one of key oncogenic drivers of lung cancer. While recent advances in targeted therapy have shown promise, effective therapy for lung cancer still remains a challenge. Given the demonstrated efficacy of BET bromodomain inhibitors in treatment of hematologic malignancies and the emerging clinical benefit of immunotherapeutic agents such as anti-PD1 antibody, we sought to determine whether a combinatorial approach involving these agents could synergize to promote anti-tumor response in genetically engineered mouse model of NSCLC harboring activating kras mutation. Upon administration of the BET bromodomain inhibitor JQ1, and/or α-PD-1 antibody, we evaluated by FACS, the dynamics of tumor-associated immune cells. Notably, treatment with JQ1 alone or in combination with α-PD1 resulted in increased CD8:Treg ratio in the tumors, likely due to the reduced proportions of Treg cells. Interestingly, while JQ1 treatment alone led to remarkable down-regulation of PD-1, α-PD1 treatment resulted in augmented T cell activation evidenced by increased expression of CD69 on tumor-CD8+ T cells. When tested ex-vivo, T cells isolated from tumors of double agent therapy showed the most enhanced ability to secrete IFN-γ relative to either agent alone. Lastly, in survival studies, the combination of both drugs was superior in reducing tumor burden and prolonged the survival of tumor-bearing mice demonstrating a synergistic effect between the two agents. Collectively, our findings highlight the therapeutic potential of combining BET bromodomain inhibition with immune checkpoint blockade for treatment of solid malignancies such as lung adenocarcinomas.