Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer

• Published in: Cell metabolism 2023-01, Vol.35 (1), p.134-149.e6
• Main Authors: Bell, Hannah N., Huber, Amanda K., Singhal, Rashi, Korimerla, Navyateja, Rebernick, Ryan J., Kumar, Roshan, El-derany, Marwa O., Sajjakulnukit, Peter, Das, Nupur K., Kerk, Samuel A., Solanki, Sumeet, James, Jadyn G., Kim, Donghwan, Zhang, Li, Chen, Brandon, Mehra, Rohit, Frankel, Timothy L., Győrffy, Balázs, Fearon, Eric R., Pasca di Magliano, Marina, Gonzalez, Frank J., Banerjee, Ruma, Wahl, Daniel R., Lyssiotis, Costas A., Green, Michael, Shah, Yatrik M.
• Format: Article
• Language: English
• Subjects: Ammonia; Animals; cancer metabolism; Colorectal Neoplasms - pathology; Immunotherapy; Mice; T-Cell Exhaustion; T-Lymphocytes; Tumor Microenvironment
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2022.11.013

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. [Display omitted] •Autochthonous metastatic mouse model of colon cancer is refractory to immunotherapy•Ammonia accumulates in tumors and reduces T cell function in vitro and in vivo•Ammonia decreases T cell transsulfuration leading to altered redox status•Clearance of ammonia reactivates T cells and decreases colorectal cancer Bell et al. identify that ammonia accumulates in colon tumors. The accumulated ammonia reduces tumor immune response by specifically inhibiting T cell function. Removing microenvironmental ammonia reactivates T cells, decreases tumor size, and re-sensitizes tumors to immunotherapy.