ACSS2 inhibitors act as metabo-immunomodulators in triple negative breast cancer [scRNA-Seq]

Acetate metabolism is an important metabolic pathway in many types of cancers and is primarily controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. However, the consequences of inhibiting tumor acetate metabolism on the tumor microenvironment and anti-tumor immunity are unknown. Herein we demonstrate that the growth of ACSS2 deficient triple negative breast cancer is severely impaired when host immunity is intact and, in many instances, ACSS2 deficient tumors are fully cleared by the immune system. Pharmacological inhibition of ACSS2 using a potent small molecule inhibitor reproduces these effects and enhances the efficacy of standard of care chemotherapy for TNBC. Single cell RNA sequencing of vehicle versus ACSS2 inhibitor treated tumors indicates differentiation and activation of T cells suggesting a crosstalk between acetate metabolism and immune cells in the tumor microenvironment. Our data suggest that blocking ACSS2 and acetate metabolism in tumors increases the availability of acetate in the tumor microenvironment. Tumor infiltrating T cells can then use acetate as a fuel source due to the relatively high expression of acetyl-CoA synthetase 1 (ACSS1), which is impervious to ACSS2 inhibitors. In this manner, ACSS1-driven oxidation of acetate in T cells helps to metabolically bolster anti-tumor immune responses. Based on our findings, we propose a completely novel paradigm for ACSS2 inhibitors as metaboimmunomodulators that dually act as inhibitors of tumor cell metabolism and modulators of tumor immunity. RNA-seq of different Bmal1 status

乙酸代谢（acetate metabolism）是多种癌症中重要的代谢通路，主要由乙酰辅酶A合成酶2（acetyl-CoA synthetase 2, ACSS2）调控，该酶可催化乙酸向乙酰辅酶A的转化。然而，抑制肿瘤乙酸代谢对肿瘤微环境及抗肿瘤免疫的影响尚不明确。本研究证实，当宿主免疫功能完整时，ACSS2缺陷型三阴性乳腺癌（triple negative breast cancer, TNBC）的生长会受到显著抑制；在多数情况下，ACSS2缺陷型肿瘤可被免疫系统完全清除。采用强效小分子抑制剂对ACSS2进行药理学抑制，可重现上述表型，并提升三阴性乳腺癌标准化疗方案的疗效。对赋形剂组与ACSS2抑制剂处理组的肿瘤进行单细胞RNA测序（single cell RNA sequencing, scRNA-seq）分析，结果显示T细胞发生分化与活化，提示肿瘤微环境中乙酸代谢与免疫细胞存在交互调控。本研究数据显示，阻断肿瘤内的ACSS2与乙酸代谢，可提升肿瘤微环境内乙酸的可获得性。由于肿瘤浸润性T细胞高表达不受ACSS2抑制剂影响的乙酰辅酶A合成酶1（acetyl-CoA synthetase 1, ACSS1），这些T细胞可将乙酸作为能量底物。在此机制下，T细胞内由ACSS1介导的乙酸氧化过程，可在代谢层面增强抗肿瘤免疫应答。基于上述研究结果，我们提出了一种全新的研究范式：ACSS2抑制剂可作为代谢免疫调节剂，同时兼具肿瘤细胞代谢抑制剂与肿瘤免疫调节剂的双重功能。不同Bmal1状态下的RNA测序