Gut microbiome drives success of immunotherapy

November 05, 2015

Why some patients respond well to immunotherapy and others do not is unclear, but two new studies now provide evidence that the gut microbiome can play a role. In one case, Marie Vetizou et al. studied the efficacy of the immunotherapy agent anti-CTLA4 9D9 Ab (ipilimumab) against established sarcomas in mice under specific pathogen-free (SPF) and germ-free (GF) conditions, finding that ipilimumab treated SPF but not GF mice. As well, the authors found that antibiotics compromised the antitumor effects of ipilimumab. Analyzing ribosomal RNA of feces revealed that a single injection of ipilimumab significantly affected the microbiome, causing a decrease of the species Bacteroidales and Burkholderiales. Replenishing the lost microbes in germ-free and antibiotic-treated mice restored the anti-cancer effects of ipilimumab treatment. To test these results in clinical practice, the researchers took fecal samples from of 25 individuals with metastatic melanoma, categorizing samples based on the presence of Bacteroidales. The team then transplanted the fecal samples into germ-free mice, and two weeks later, treated them with ipilimumab. Tumors growing in mice that had been transplanted with feces from patients with a higher percentage of B. fragilis responded better to the treatment than their counterparts.

A similar relationship between gut microbiome composition and response to anti-cancer treatment was found by Ayelet Sivan and colleagues. To understand any effects of the microbiota on treatment of anti-PD-1/PD-L1 monoclonal antibodies for melanoma, the authors studied two groups of mice: Jackson Laboratory (JAX) and Taconic Farms (TAC) mice, each of which is known to harbor unique sets of gut microbes. They noted tumor-specific T cell responses in the TAC mice that resulted in more aggressive tumor growth, as well as more CD8+ T cell accumulation within the tumors. Fecal transplants from JAX to TAC mice slowed the tumor growth in TAC mice, and these transplants -- in combination with PD-L1 antibodies - further improved tumor control. A closer look at the JAX microbiome revealed a 400-fold abundance of Bifidobacterium, which showed a positive association with anti-tumor T cell responses. Genome-wide transcriptional profiling of mice harboring this bacteria showed upregulation of several genes that are critical for anti-tumor responses. Collectively, these two studies demonstrate that the gut microbiome could play an important role in facilitating immunotherapy for cancer.
Article #26: "Anticancer immunotherapy by CTLA4 blockade relies on the gut microbiota," by M. Vétizou; J.M. Pitt; R. Daillère; N. Waldschmitt; C. Flament; S. Rusakiewicz; B. Routy; M.P. Roberti; C. Doung; V. Poirier-Colame; A. Roux; S. Becharef; T. Yamazaki; N. Jacquelot; D.P. Enot; P. Opolon; A. Eggermont; P.-L. Woerther; E. Chachaty; N.Chaput; C. Robert; C. Matteus; G. Kroemer; L. Zitvogel at Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC) in Villejuif, France; M. Vétizou; J.M. Pitt; R. Daillère; C. Flament; S. Rusakiewicz; B. Routy; M.P. Roberti; C. Doung; V. Poirier-Colame; A. Roux; S. Becharef; T. Yamazaki; N. Jacquelot; A. Eggermont; C. Robert; G. Kroemer; I.G. Boneca; L. Zitvogel; N. Chaput at INSERM in Villejuif, France. For a complete list of authors, see the manuscript.

American Association for the Advancement of Science

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