Schofield James H, Longo Joseph, Sheldon Ryan D, Albano Emma, Hawk Mark A, Murphy Sean, Duong Loan, Rahmy Sharif, Lu Xin, Jones Russell G, Schafer Zachary T
Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556 USA.
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, Michigan 49503, USA.
bioRxiv. 2023 Sep 17:2023.09.14.557799. doi: 10.1101/2023.09.14.557799.
Targeting PD-1 is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment (TME). Here, we find that αPD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1). Acod1 has an important role in the resistance to αPD-1, as decreasing Acod1 levels in αPD-1 resistant cancer cells can sensitize tumors to αPD-1 therapy. Mechanistically, cancer cells with high Acod1 inhibit the proliferation of naïve CD8 T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8 T cell proliferation is not dependent on secretion of ITA, but is instead a consequence of the release of small inhibitory peptides. Our study suggests that strategies to counter the activity of Acod1 in cancer cells may sensitize tumors to ICB therapy.
靶向程序性死亡蛋白1（PD-1）是许多免疫检查点阻断（ICB）治疗方法的重要组成部分。然而，ICB在多种癌症类型中并非有效的策略，部分原因是肿瘤微环境（TME）中的免疫抑制代谢产物。在此，我们发现αPD-1耐药癌细胞由于乌头酸脱羧酶（Acod1）水平升高而产生大量衣康酸（ITA）。Acod1在对αPD-1的耐药性中起重要作用，因为降低αPD-1耐药癌细胞中的Acod1水平可使肿瘤对αPD-1治疗敏感。从机制上讲，Acod1水平高的癌细胞通过分泌抑制因子抑制幼稚CD8 T细胞的增殖。令人惊讶的是，CD8 T细胞增殖的抑制不依赖于ITA的分泌，而是小抑制肽释放的结果。我们的研究表明，对抗癌细胞中Acod1活性的策略可能使肿瘤对ICB治疗敏感。
