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Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8+ T cell effector

Jingjing Cong1, Pianpian Liu2, Zili Han2

  • 1Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Department of Digestive Disease, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China.

Immunity
|March 13, 2024
PubMed

Insights

Elevated deoxycholic acid (DCA) from gut microbes impairs CD8+ T cell anti-tumor immunity in colorectal cancer (CRC). Disrupting DCA metabolism restores T cell function and inhibits tumor growth, offering new therapeutic strategies.

Area of Science:

  • Microbiology
  • Immunology
  • Oncology

Background:

  • Secondary bile acid deoxycholic acid (DCA) is elevated in colorectal cancer (CRC).
  • The role of DCA in CRC pathogenesis and its impact on anti-tumor immunity are not well understood.

Purpose of the Study:

  • To investigate the role of gut microbiota-derived deoxycholic acid (DCA) in regulating CD8+ T cell effector function in colorectal cancer (CRC).
  • To elucidate the underlying mechanisms of DCA-mediated immune suppression.
  • To explore therapeutic strategies targeting microbial DCA metabolism for CRC treatment.

Main Methods:

  • Screening of gut microbiota-derived metabolites to identify regulators of CD8+ T cell function.
  • Investigating the molecular mechanism of DCA action on CD8+ T cells, focusing on calcium signaling pathways.
  • Correlating DCA levels and bacterial DCA gene expression with CD8+ T cell function in CRC patients.
  • Utilizing mouse models of CRC to assess the impact of bacterial DCA production on tumor growth and immune response.
  • Employing interventions such as bile acid chelation, genetic disruption of DCA biosynthesis, and bacteriophage therapy to modulate DCA metabolism.

Main Results:

  • Deoxycholic acid (DCA) was identified as a negative regulator of CD8+ T cell effector function.
  • DCA suppresses CD8+ T cell responses by inhibiting Ca2+-NFAT2 signaling via targeting plasma membrane Ca2+ ATPase (PMCA).
  • In CRC patients, CD8+ T cell function inversely correlated with DCA concentration and bacterial DCA biosynthetic gene expression.
  • Gut bacteria producing DCA suppressed CD8+ T cell function and promoted tumor growth in mice.
  • Interventions disrupting bile acid metabolism, including bile acid chelation, genetic ablation of DCA biosynthesis, or bacteriophage treatment, abolished the tumor-promoting effects of DCA.

Conclusions:

  • Microbial DCA metabolism causally links to suppressed anti-tumor CD8+ T cell responses in CRC.
  • Targeting microbial DCA metabolism represents a promising therapeutic avenue for enhancing anti-tumor immunity in colorectal cancer.
Keywords:
CD8(+) T cellanti-tumor immunitydeoxycholic acideffector functionmicrobiota

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