Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota

Abstract

Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis–specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.

Culture of previously uncultured members of the human gut microbiota by culturomics

“…However, a growing problem is the gaps that remain in metagenomics, which correspond to unidentified sequences that may be correlated with an identified organism 9 . Moreover, the exploration of relations between the microbiota and human health require-both for an experimental model and therapeutic strategies-the growing of microorganisms in pure culture 10 , as recently demonstrated in elucidations of the role of Clostridium butyricum in necrotizing enterocolitis and the influence of gut microbiota on cancer immunotherapy effects 11,12 . In recent years, microbial culture techniques have been neglected, which explains why the known microbial community of the human gut is extremely low 13 .…”

The human gut microbiome as source of innovation for health: Which physiological and therapeutic outcomes could we expect?

“…Other examples of essential prediction of treatment outcome come from the recognition of the impact of donor microbiota diversity and relative risk of premature death after hematopoietic stem cell transplantation [68], or between gut microbiome and prediction of chemotherapy-related bloodstream infection risk [69]. Finally, this stratification tool was elegantly exploited with the metagenome-profiling studies of patients that respond to the anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and anti-programmed death 1 (PD-1) immune checkpoint inhibitors [70,71] and to cycloheximide [72]. This is being translated into the clinical practice in order to give efficient but toxic treatments only to patients that have a strong responder profile, and opens perspective of promoting responder profiles by adding live biotherapeutics (see below).…”

The gut microbiota and immune checkpoint inhibitors

“…In mice reared under either specific pathogen free (SPF) conditions, germ-free (GF) conditions, or in antibiotic-treated mice models, the authors found that the efficacy of anti-CTLA-4 Ab was impaired without the presence of gut commensal bacteria and was significantly higher with the colonization of two species from the Bacteroidales order (Bacteroidetes phylum) and one species from the Burkholderiale s order (Proteobacteria phylum). Additionally, these studies suggested that two species from the Bacteroidales and Burkholderiales order significantly reduced the histopathological signs of colitis, 3 a common, high-risk, immune-related adverse event associated with anti-CTLA-4 Ab therapy. 4-7 While there is supportive evidence that species from the Bacteroidales order are associated with decreased incidence of colitis in patients administered anti-CTLA-4 Ab, 8 there is also data correlating the colonization of certain Bacteroidales species in the gut with colitis 9 , 10 and Crohn's disease.…”

“…35 , 36 A study by Herold and colleagues in December 2017 found systemic immune activation in humanized mice models given anti-CD3 mAb in combination with antibiotics, shown through elevated numbers of effector T-cells and IFN-γ, decreased production of IL-10, and the presence of anti-nuclear antibodies. 35 While there are other investigations demonstrating that gut dysbiosis, or a microbial imbalance or modification in the host gut, may counteract the effects of both immunosuppressive 35 and immunostimulatory drugs, 3 , 23 , 27 , 37 , 38 it may be that microbiota have a more potent or direct interaction with the immune checkpoint drugs rather than the immunomodulatory cells involved per se. All in all, these apparent contradictions reinforce that the function and mechanisms by which commensal bacteria communicate with the immune system are poorly understood and remain a fascinating challenge for prospective researchers.…”