Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Department of Chemistry, Northwestern University, Evanston, IL, USA.
Sci Adv. 2024 Nov 29;10(48):eadq8122. doi: 10.1126/sciadv.adq8122. Epub 2024 Nov 27.
Numerous human cancers have exhibited the ability to elude immune checkpoint blockade (ICB) therapies. This type of resistance can be mediated by immune-suppressive macrophages that limit antitumor immunity in the tumor microenvironment (TME). Here, we elucidate a strategy to shift macrophages into a proinflammatory state that down-regulates V domain immunoglobulin suppressor of T cell activation (VISTA) via inhibiting AhR and IRAK1. We used a high-throughput microfluidic platform combined with a genome-wide CRISPR knockout screen to identify regulators of VISTA levels. Functional characterization showed that the knockdown of these hits diminished VISTA surface levels on macrophages and sustained an antitumor phenotype. Furthermore, targeting of both AhR and IRAK1 in mouse models overcame resistance to ICB treatment. Tumor immunophenotyping indicated that infiltration of cytotoxic CD8 cells, natural killer cells, and antitumor macrophages was substantially increased in treated mice. Collectively, AhR and IRAK1 are implicated as regulators of VISTA that coordinate a multifaceted barrier to antitumor immune responses.
许多人类癌症表现出逃避免疫检查点阻断（ICB）治疗的能力。这种类型的耐药性可以由免疫抑制性巨噬细胞介导，这些巨噬细胞在肿瘤微环境（TME）中限制抗肿瘤免疫。在这里，我们阐明了一种通过抑制 AhR 和 IRAK1 将巨噬细胞转化为促炎状态的策略，从而下调 V 结构域免疫球蛋白 T 细胞激活抑制剂（VISTA）。我们使用高通量微流控平台结合全基因组 CRISPR 敲除筛选来鉴定 VISTA 水平的调节剂。功能特征表明，这些靶点的敲低降低了巨噬细胞表面的 VISTA 水平，并维持了抗肿瘤表型。此外，在小鼠模型中靶向 AhR 和 IRAK1 克服了对 ICB 治疗的耐药性。肿瘤免疫表型分析表明，在治疗小鼠中，细胞毒性 CD8 细胞、自然杀伤细胞和抗肿瘤巨噬细胞的浸润显著增加。总之，AhR 和 IRAK1 被认为是 VISTA 的调节剂，协调抗肿瘤免疫反应的多方面障碍。
