Sex bias exists in the development and progression of non-reproductive organ cancers, but the underlying mechanisms are enigmatic. Studies so far have focused largely on sexual dimorphisms in cancer biology and socioeconomic factors. Here, we establish a role for CD8 + T cell-dependent anti-tumor immunity in mediating sex differences in tumor aggressiveness, which is driven by the gonadal androgen but not sex chromosomes. A male bias exists in the frequency of intratumoral antigen-experienced Tcf7 /TCF1 + progenitor exhausted CD8 + T cells that are devoid of effector activity as a consequence of intrinsic androgen receptor (AR) function. Mechanistically, we identify a novel sex-specific regulon in progenitor exhausted CD8 + T cells and a pertinent contribution from AR as a direct transcriptional trans-activator of Tcf7 /TCF1. The T cell intrinsic function of AR in promoting CD8 + T cell exhaustion in vivo was established using multiple approaches including loss-of-function studies with CD8-specific Ar knockout mice. Moreover, ablation of the androgen-AR axis rewires the tumor microenvironment to favor effector T cell differentiation and potentiates the efficacy of anti-PD-1 immune checkpoint blockade. Collectively, our findings highlight androgen-mediated promotion of CD8 + T cell dysfunction in cancer and imply broader opportunities for therapeutic development from understanding sex disparities in health and disease.

中文翻译：

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雄激素与 CD8 + T 细胞耗竭程序协同作用，导致癌症中的性别偏见

非生殖器官癌症的发生和进展中存在性别偏见，但其潜在机制却很神秘。迄今为止的研究主要集中在癌症生物学和社会经济因素中的性别二态性。这里，我们为CD8建立一个角色+T 细胞依赖性抗肿瘤免疫介导肿瘤侵袭性的性别差异，这是由性腺雄激素而非性染色体驱动的。瘤内抗原经历的频率存在男性偏差TCF7/TCF1+祖细胞耗竭 CD8+由于内在雄激素受体 (AR) 功能而缺乏效应活性的 T 细胞。从机制上讲，我们在祖细胞耗尽的 CD8 中发现了一种新的性别特异性调节子+T 细胞和 AR 作为直接转录反式激活剂的相关贡献TCF7/TCF1。AR促进CD8的T细胞内在功能+使用多种方法建立体内 T 细胞耗竭，包括 CD8 特异性功能丧失研究氩气基因敲除小鼠。此外，雄激素-AR轴的消融会重新连接肿瘤微环境，以有利于效应T细胞分化，并增强抗PD-1免疫检查点阻断的功效。总的来说，我们的研究结果强调了雄激素介导的 CD8 促进作用+癌症中的 T 细胞功能障碍，意味着通过了解健康和疾病中的性别差异，可以为治疗开发提供更广泛的机会。