Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Cancer Discov. 2023 Sep 6;13(9):2090-2105. doi: 10.1158/2159-8290.CD-22-0869.
Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8+ T cells in the tumor. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD-1 treatment. Moreover, increased T-cell exhaustion was observed in male GBM patients. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, partially mediated by the X chromosome inactivation escape gene Kdm6a. These findings demonstrate that sex-biased predetermined behavior of T cells is critical for inducing sex differences in GBM progression and immunotherapy response.
Immunotherapies in patients with GBM have been unsuccessful due to a variety of factors, including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-biased T-cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve the therapeutic efficacy of immunotherapy in GBM. See related commentary by Alspach, p. 1966. This article is featured in Selected Articles from This Issue, p. 1949.
胶质母细胞瘤（GBM）的发病率和结局存在明显的性别差异，新出现的证据表明，这些差异扩展到遗传/表观遗传和细胞差异，包括免疫反应。然而，驱动免疫性别差异的机制尚未完全阐明。在这里，我们证明 T 细胞在驱动 GBM 性别差异方面起着关键作用。雄性小鼠表现出肿瘤生长加速，肿瘤中 CD8+T 细胞的频率降低，耗竭增加。此外，在男性中发现祖细胞耗竭 T 细胞的频率更高，对抗 PD-1 治疗的反应性提高。此外，在男性 GBM 患者中观察到 T 细胞耗竭增加。骨髓嵌合体和过继转移模型表明，T 细胞介导的肿瘤控制主要以细胞内在方式调节，部分由 X 染色体失活逃逸基因 Kdm6a 介导。这些发现表明，T 细胞的性别偏置预定行为对于诱导 GBM 进展和免疫治疗反应的性别差异至关重要。
由于多种因素的影响，包括 GBM 中高度免疫抑制的肿瘤微环境，免疫疗法在 GBM 患者中的应用一直不成功。这项研究表明，T 细胞的性别偏置行为主要是内在调节的，进一步表明可以利用性别特异性方法来提高免疫疗法在 GBM 中的治疗效果。请参阅本期相关评论文章，第 1966 页。本文选自本期精选文章，第 1949 页。
