Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia.
Section of Hematology/Oncology, Departmentof Medicine, University of Chicago, Chicago, Illinois.
Mol Cancer Ther. 2023 Jun 1;22(6):751-764. doi: 10.1158/1535-7163.MCT-22-0369.
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. We performed bioinformatics analysis to elucidate the impact of endogenous Rb LOF on the immune TME in human primary and metastatic tumors. Next, we used isogenic murine models of Rb-deficient prostate cancer 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. 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 IFN signaling within tumor cells, resulting in differential macrophage and T-cell-mediated tumor growth inhibition and sensitization of Rb-deficient prostate cancer to ICB. BETi can reprogram the immunologically cold Rb-deficient TME via STING/NF-κB/IFN signaling to sensitize Rb-deficient prostate cancer to ICB. These data provide the mechanistic rationale to test combinations of BETi and ICB in clinical trials of Rb-deficient prostate cancer.
非 T 细胞炎症免疫“冷”肿瘤微环境（TME）与对免疫检查点阻断（ICB）的反应不佳有关，并且可以通过肿瘤细胞基因组学进行塑造。在这里，我们评估了视网膜母细胞瘤（Rb）肿瘤抑制因子功能丧失（LOF）如何改变 TME，以及靶向 Rb 缺失的分子后果的治疗策略是否增强 ICB 疗效。我们进行了生物信息学分析，以阐明内源性 Rb LOF 对人类原发性和转移性肿瘤免疫 TME 的影响。接下来，我们使用 Rb 缺陷前列腺癌的同源小鼠模型进行体外和体内机制研究，以研究 Rb 缺失和溴结构域和末端结构域（BET）抑制（BETi）如何重新编程免疫景观，并评估 BETi 的体内治疗效果，单独使用和与 ICB 和雄激素剥夺疗法联合使用。Rb 缺失在非 T 细胞炎症肿瘤中富集，Rb 缺陷的小鼠肿瘤在体内表现出免疫浸润减少。BETi JQ1 通过增强肿瘤细胞 STING/NF-κB 激活和肿瘤细胞内的 I 型 IFN 信号传导，增加 TME 中的免疫浸润，导致巨噬细胞和 T 细胞介导的肿瘤生长抑制的差异，并使 Rb 缺陷的前列腺癌对 ICB 敏感。BETi 可以通过 STING/NF-κB/IFN 信号转导重新编程免疫冷的 Rb 缺陷 TME，使 Rb 缺陷的前列腺癌对 ICB 敏感。这些数据为在 Rb 缺陷前列腺癌的临床试验中测试 BETi 和 ICB 的组合提供了机制依据。
