美国密歇根大学Yatrik M. Shah研究团队发现，微环境中的氨增强结直肠癌的T细胞衰竭。2022年12月16日，国际知名学术期刊《细胞—代谢》发表了这一成果。

Title: Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer

Author: Hannah N. Bell, Amanda K. Huber, Rashi Singhal, Navyateja Korimerla, Ryan J. Rebernick, Roshan Kumar, Marwa O. El-derany, Peter Sajjakulnukit, Nupur K. Das, Samuel A. Kerk, Sumeet Solanki, Jadyn G. James, Donghwan Kim, Li Zhang, Brandon Chen, Rohit Mehra, Timothy L. Frankel, Balázs Gyrffy, Eric R. Fearon, Marina Pasca di Magliano, Frank J. Gonzalez, Ruma Banerjee, Daniel R. Wahl, Costas A. Lyssiotis, Michael Green, Yatrik M. Shah

Issue&Volume: 2022-12-16

Abstract: Effective therapies are lacking for patients with advanced colorectal cancer (CRC).The CRC tumor microenvironment has elevated metabolic waste products due to alteredmetabolism and proximity to the microbiota. The role of metabolite waste in tumordevelopment, progression, and treatment resistance is unclear. We generated an autochthonousmetastatic mouse model of CRC and used unbiased multi-omic analyses to reveal a robustaccumulation of tumoral ammonia. The high ammonia levels induce T cell metabolic reprogramming,increase exhaustion, and decrease proliferation. CRC patients have increased serumammonia, and the ammonia-related gene signature correlates with altered T cell response,adverse patient outcomes, and lack of response to immune checkpoint blockade. We demonstratethat enhancing ammonia clearance reactivates T cells, decreases tumor growth, andextends survival. Moreover, decreasing tumor-associated ammonia enhances anti-PD-L1efficacy. These findings indicate that enhancing ammonia detoxification can reactivateT cells, highlighting a new approach to enhance the efficacy of immunotherapies.

DOI: 10.1016/j.cmet.2022.11.013

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00504-6