Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA.
Cell Rep. 2024 Apr 23;43(4):113984. doi: 10.1016/j.celrep.2024.113984. Epub 2024 Mar 24.
Targeting programmed cell death protein 1 (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. 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 naive CD8 T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8 T cell proliferation is not dependent on the 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不是一种有效的策略，部分原因是肿瘤微环境中的免疫抑制代谢物。在这里，我们发现 αPD-1 耐药的癌细胞由于 aconitate decarboxylase（Acod1）水平升高而产生大量的 itaconate（ITA）。Acod1 在抵抗 αPD-1 中起着重要作用，因为降低 αPD-1 耐药癌细胞中的 Acod1 水平可以使肿瘤对 αPD-1 治疗敏感。从机制上讲，高 Acod1 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，抑制 CD8 T 细胞增殖不依赖于 ITA 的分泌，而是由于小抑制肽的释放所致。我们的研究表明，对抗癌细胞中 Acod1 活性的策略可能会使肿瘤对 ICB 治疗敏感。
