Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer

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 Győrffy; Eric R Fearon; Marina Pasca di Magliano; Frank J Gonzalez; Ruma Banerjee; Daniel R Wahl; Costas A Lyssiotis; Michael Green; Yatrik M Shah

doi:10.1016/j.cmet.2022.11.013

Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer

Cell Metab. 2023 Jan 3;35(1):134-149.e6. doi: 10.1016/j.cmet.2022.11.013. Epub 2022 Dec 16.

Authors

Hannah N Bell¹, Amanda K Huber², Rashi Singhal¹, Navyateja Korimerla³, Ryan J Rebernick⁴, Roshan Kumar⁵, Marwa O El-Derany⁶, Peter Sajjakulnukit¹, Nupur K Das¹, Samuel A Kerk¹, Sumeet Solanki¹, Jadyn G James², Donghwan Kim⁷, Li Zhang¹, Brandon Chen¹, Rohit Mehra⁸, Timothy L Frankel⁹, Balázs Győrffy¹⁰, Eric R Fearon¹¹, Marina Pasca di Magliano⁹, Frank J Gonzalez⁷, Ruma Banerjee⁵, Daniel R Wahl³, Costas A Lyssiotis¹², Michael Green¹³, Yatrik M Shah¹⁴

Affiliations

¹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
³ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA.
⁶ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
⁷ Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Department of Bioinformatics and 2(nd) Department of Pediatrics, Semmelweis University, Budapest, Hungary; TTK Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary.
¹¹ University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
¹² Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
¹³ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Veteran's Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA.
¹⁴ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. Electronic address: shahy@umich.edu.

Abstract

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.

Keywords: ammonia; cancer metabolism; immunotherapy; tumor microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Ammonia*
Animals
Colorectal Neoplasms* / pathology
Immunotherapy
Mice
T-Cell Exhaustion
T-Lymphocytes
Tumor Microenvironment

Substances

Ammonia

Abstract

Publication types

MeSH terms

Substances

Grants and funding