Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Villejuif, France.
Cell Death Differ. 2023 Dec;30(12):2447-2451. doi: 10.1038/s41418-023-01232-y. Epub 2023 Oct 16.
BCL2 is an apoptosis-inhibitory oncoprotein that also possesses apoptosis-unrelated activities. Pharmacological BCL2 inhibitors have been developed with the scope of driving BCL2-dependent cancer cells into apoptosis, and one BCL2 antagonist, venetoclax, has been clinically approved for the treatment of specific leukemias and lymphomas. Nonetheless, it appears that venetoclax, as well as genetic BCL2 inhibition, can mediate anticancer effects through an indirect action. Such an indirect effect relies on the enhancement of the immunostimulatory function of dendritic cells, hence increasing tumor immunosurveillance. Mechanistically, BCL2 inhibition involves improved antigen presentation by conventional type-1 dendritic cells (cDC1s) due to the activation of an interferon response, leading to a T cell-mediated anticancer immune response that can be further enhanced by PD-1 blockade. These findings support the emerging hypothesis that successful antineoplastic drugs generally mediate their effects indirectly, through the immune system, rather via merely cell-autonomous effects on malignant cells.
BCL2 是一种凋亡抑制致癌蛋白，它还具有与凋亡无关的活性。已经开发出了药理学 BCL2 抑制剂，旨在诱导 BCL2 依赖性癌细胞凋亡，其中一种 BCL2 拮抗剂 venetoclax 已被临床批准用于治疗特定的白血病和淋巴瘤。然而，venetoclax 以及基因 BCL2 抑制似乎可以通过间接作用介导抗癌作用。这种间接作用依赖于树突状细胞免疫刺激功能的增强，从而增加肿瘤免疫监视。从机制上讲，BCL2 抑制涉及由于干扰素反应的激活而导致常规 1 型树突状细胞 (cDC1s) 的抗原呈递改善，从而导致 T 细胞介导的抗癌免疫反应，通过 PD-1 阻断可进一步增强这种反应。这些发现支持了一个新兴假说，即成功的抗肿瘤药物通常通过免疫系统间接介导其作用，而不是通过对恶性细胞的单纯细胞自主作用。
