Department of Microbiology and Immunology, Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
Cancer Immunol Res. 2023 Jan 3;11(1):38-55. doi: 10.1158/2326-6066.CIR-22-0116.
V domain immunoglobulin suppressor of T-cell activation (VISTA) is a premier target for cancer treatment due to its broad expression in many cancer types and enhanced expression upon development of adaptive immune checkpoint resistance. In the CT26 colorectal cancer model, monotherapy of small tumors with anti-VISTA resulted in slowed tumor growth. In a combination therapy setting, large CT26 tumors showed complete adaptive resistance to anti-PD-1/CTLA-4, but inclusion of anti-VISTA led to rejection of half the tumors. Mechanisms of enhanced antitumor immunity were investigated using single-cell RNA sequencing (scRNA-seq), multiplex image analysis, and flow cytometry of the tumor immune infiltrate. In both treatment models, anti-VISTA upregulated stimulated antigen presentation pathways and reduced myeloid-mediated suppression. Imaging revealed an anti-VISTA stimulated increase in contacts between T cells and myeloid cells, further supporting the notion of increased antigen presentation. scRNA-seq of tumor-specific CD8+ T cells revealed that anti-VISTA therapy induced T-cell pathways highly distinct from and complementary to those induced by anti-PD-1 therapy. Whereas anti-CTLA-4/PD-1 expanded progenitor exhausted CD8+ T-cell subsets, anti-VISTA promoted costimulatory genes and reduced regulators of T-cell quiescence. Notably, this is the first report of a checkpoint regulator impacting CD8+ T-cell quiescence, and the first indication that quiescence may be a target in the context of T-cell exhaustion and in cancer. This study builds a foundation for all future studies on the role of anti-VISTA in the development of antitumor immunity and provides important mechanistic insights that strongly support use of anti-VISTA to overcome the adaptive resistance seen in contemporary treatments involving PD-1 and/or CTLA-4. See related Spotlight by Wei, p. 3.
V 结构域免疫球蛋白抑制 T 细胞活化因子（VISTA）因其在多种癌症类型中的广泛表达以及在适应性免疫检查点抵抗发展时表达增强，成为癌症治疗的首选靶标。在 CT26 结直肠癌模型中，抗 VISTA 单药治疗小肿瘤导致肿瘤生长减缓。在联合治疗方案中，大 CT26 肿瘤对抗 PD-1/CTLA-4 完全产生适应性抵抗，但加入抗 VISTA 导致一半肿瘤被排斥。使用单细胞 RNA 测序（scRNA-seq）、多重图像分析和肿瘤免疫浸润的流式细胞术研究了增强抗肿瘤免疫的机制。在两种治疗模型中，抗 VISTA 上调了刺激的抗原呈递途径并减少了髓样细胞介导的抑制。成像显示抗 VISTA 刺激 T 细胞和髓样细胞之间的接触增加，进一步支持了抗原呈递增加的观点。肿瘤特异性 CD8+T 细胞的 scRNA-seq 显示，抗 VISTA 治疗诱导的 T 细胞途径与抗 PD-1 治疗诱导的途径高度不同但互补。虽然抗 CTLA-4/PD-1 扩增祖细胞耗尽的 CD8+T 细胞亚群，但抗 VISTA 促进共刺激基因并减少 T 细胞静止的调节剂。值得注意的是，这是第一个报道检查点调节剂影响 CD8+T 细胞静止的报告，也是第一个表明在 T 细胞耗竭和癌症的背景下，静止可能是一个靶点的迹象。这项研究为未来所有关于抗 VISTA 在抗肿瘤免疫发展中的作用的研究奠定了基础，并提供了重要的机制见解，强烈支持使用抗 VISTA 来克服涉及 PD-1 和/或 CTLA-4 的当代治疗中观察到的适应性抵抗。见相关的 Wei 等人的观点文章，第 3 页。
