Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
Cell Metab. 2023 Jan 3;35(1):134-149.e6. doi: 10.1016/j.cmet.2022.11.013. Epub 2022 Dec 16.
Effective therapies are lacking for patients with advanced colorectal cancer (CRC). The CRC tumor microenvironment has elevated metabolic waste products due to altered metabolism and proximity to the microbiota. The role of metabolite waste in tumor development, progression, and treatment resistance is unclear. We generated an autochthonous metastatic mouse model of CRC and used unbiased multi-omic analyses to reveal a robust accumulation of tumoral ammonia. The high ammonia levels induce T cell metabolic reprogramming, increase exhaustion, and decrease proliferation. CRC patients have increased serum ammonia, and the ammonia-related gene signature correlates with altered T cell response, adverse patient outcomes, and lack of response to immune checkpoint blockade. We demonstrate that enhancing ammonia clearance reactivates T cells, decreases tumor growth, and extends survival. Moreover, decreasing tumor-associated ammonia enhances anti-PD-L1 efficacy. These findings indicate that enhancing ammonia detoxification can reactivate T cells, highlighting a new approach to enhance the efficacy of immunotherapies.
对于晚期结直肠癌 (CRC) 患者，缺乏有效的治疗方法。CRC 肿瘤微环境由于代谢改变和与微生物群的接近而产生升高的代谢废物。代谢废物在肿瘤发生、进展和治疗耐药性中的作用尚不清楚。我们生成了一种 CRC 的自发转移性小鼠模型，并使用无偏多组学分析揭示了肿瘤中氨的大量积累。高氨水平诱导 T 细胞代谢重编程，增加衰竭，减少增殖。CRC 患者的血清氨水平升高，与 T 细胞反应改变、不良患者结局以及对免疫检查点阻断无反应相关的氨相关基因特征相关。我们证明了增强氨清除可重新激活 T 细胞，减少肿瘤生长并延长生存期。此外，降低肿瘤相关氨可增强抗 PD-L1 疗效。这些发现表明增强氨解毒作用可以重新激活 T 细胞，突出了增强免疫疗法疗效的新方法。
