Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy

Science. 2020 Sep 18;369(6510):1481-1489. doi: 10.1126/science.abc3421. Epub 2020 Aug 13.


Several species of intestinal bacteria have been associated with enhanced efficacy of checkpoint blockade immunotherapy, but the underlying mechanisms by which the microbiome enhances antitumor immunity are unclear. In this study, we isolated three bacterial species-Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species-that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer. We found that intestinal B. pseudolongum modulated enhanced immunotherapy response through production of the metabolite inosine. Decreased gut barrier function induced by immunotherapy increased systemic translocation of inosine and activated antitumor T cells. The effect of inosine was dependent on T cell expression of the adenosine A2A receptor and required costimulation. Collectively, our study identifies a previously unknown microbial metabolite immune pathway activated by immunotherapy that may be exploited to develop microbial-based adjuvant therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / therapeutic use
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / immunology
  • Bifidobacterium / metabolism*
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / immunology
  • Female
  • Gastrointestinal Microbiome*
  • Immunotherapy*
  • Inosine / metabolism*
  • Intestinal Neoplasms / therapy*
  • Lactobacillus johnsonii / metabolism*
  • Male
  • Melanoma / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / therapy
  • Receptor, Adenosine A2A / metabolism
  • Skin Neoplasms / therapy*
  • T-Lymphocytes / immunology
  • Urinary Bladder Neoplasms / therapy*


  • Antibodies
  • B7-H1 Antigen
  • CTLA-4 Antigen
  • Receptor, Adenosine A2A
  • Inosine

Supplementary concepts

  • Bifidobacterium pseudolongum