BET inhibition sensitizes immunologically-cold Rb-deficient prostate cancer to immune checkpoint blockade

Abstract

Purpose: Non-T cell-inflamed immunologically-cold tumor microenvironments (TME) are associated with poor responsiveness to immune checkpoint blockade (ICB), and can be sculpted by tumor cell genomics. Here we evaluated how Retinoblastoma (Rb) tumor suppressor loss of function (LOF), one of the most frequent alterations in human cancer and associated with lineage plasticity, poor prognosis and therapeutic outcomes, alters the TME, and whether therapeutic strategies targeting the molecular consequences of Rb loss enhance ICB efficacy. Experimental Design: We performed bioinformatics analysis to elucidate the impact of endogenous Rb LOF on the immune TME in human primary and metastatic tumors. Next, we utilized isogenic murine models of Rb-deficient prostate cancer (PC) for in vitro and in vivo mechanistic studies to examine how Rb loss and bromodomain and extraterminal (BET) domain inhibition (BETi) reprograms the immune landscape, and evaluated in vivo therapeutic efficacy of BETi, singly and in combination with ICB and androgen deprivation therapy. Results: Rb loss was enriched in non-T cell-inflamed tumors, and Rb-deficient murine tumors demonstrated decreased immune infiltration in vivo. The BETi JQ1 increased immune infiltration into the TME through enhanced tumor cell STING/NF-κB activation and type I interferon (IFN) signaling within tumor cells, resulting in differential macrophage and T cell-mediated tumor growth inhibition and sensitization of Rb-deficient PC to ICB. Conclusions: BETi can reprogram the immunologically cold Rb-deficient TME via STING/NF-κB/IFN signaling to sensitize Rb-deficient PC to ICB. These data provide the mechanistic rationale to test combinations of BETi and ICB in clinical trials of Rb-deficient PC.

Disrupting prostate cancer research: Challenge accepted; report from the 2023 Coffey‐Holden Prostate Cancer Academy Meeting

“…This is especially relevant in the context of engineered immune therapies, which further modify and have unique effects on circulating immune cells and the tumor microenvironment 129–131 . There has been increasing interest in harnessing other components of the immune system to treat malignancies, including: the adaptive immune system with gamma‐delta T cells 132 and regulatory T cells 133 ; the innate immune system with CAR macrophages 134 and CAR natural killer (NK) cells 135 ; and other elements that profoundly affect the function of the immune system such as the microbiome, 136 Toll‐like receptors 137 and the STING pathways 138 . Importantly, what is learned in the pursuit of development of these therapeutic modalities for mCRPC will also impact development and success for other solid tumor‐targeting treatments and vice‐versa.…”