美国俄勒冈健康科学大学Amy E. Moran研究小组发现，T细胞中的雄性激素受体活性限制检查点阻断疗法的疗效。2022年3月23日，《自然》杂志在线发表了这项成果。

研究人员表示，免疫检查点阻断已经彻底改变了肿瘤学领域，其能够在实体肿瘤中诱导出持久的抗肿瘤免疫力。在晚期前列腺癌患者中，免疫治疗大多失败。雄性激素剥夺疗法是对这些患者进行的经典治疗，能够抑制肿瘤细胞的生长，研究人员推测这种疗法也会影响到肿瘤相关的T细胞。

研究人员证明，雄性激素受体（AR）阻断通过直接增强CD8 T细胞功能，使肿瘤宿主对有效的检查点阻断敏感。抑制CD8 T细胞的AR活性可防止T细胞耗竭，并通过增加IFNγ的表达改善对PD-1靶向治疗的反应性。AR直接与Ifng结合，用一种小分子驱逐AR可明显增加CD8 T细胞的细胞因子产生。总之，这些研究结果表明，T细胞内在的AR活性抑制IFNγ的表达，这代表了免疫疗法抗性的一种新机制。

附：英文原文

Title: Androgen receptor activity in T cells limits checkpoint blockade efficacy

Author: Guan, Xiangnan, Polesso, Fanny, Wang, Chaojie, Sehrawat, Archana, Hawkins, Reed M., Murray, Susan E., Thomas, George V., Caruso, Breanna, Thompson, Reid F., Wood, Mary A., Hipfinger, Christina, Hammond, Scott A., Graff, Julie N., Xia, Zheng, Moran, Amy E.

Issue&Volume: 2022-03-23

Abstract: Immune checkpoint blockade has revolutionized the field of oncology, inducing durable anti-tumour immunity in solid tumours. In patients with advanced prostate cancer, immunotherapy treatments have largely failed1,2,3,4,5. Androgen deprivation therapy is classically administered in these patients to inhibit tumour cell growth, and we postulated that this therapy also affects tumour-associated T cells. Here we demonstrate that androgen receptor (AR) blockade sensitizes tumour-bearing hosts to effective checkpoint blockade by directly enhancing CD8 T cell function. Inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. AR bound directly to Ifng and eviction of AR with a small molecule significantly increased cytokine production in CD8 T cells. Together, our findings establish that T cell intrinsic AR activity represses IFNγ expression and represents a novel mechanism of immunotherapy resistance.

DOI: 10.1038/s41586-022-04522-6

Source: https://www.nature.com/articles/s41586-022-04522-6