Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab

Ipilimumab, an immune checkpoint inhibitor targeting CTLA-4, prolongs survival in a subset of patients with metastatic melanoma but can induce immune-related adverse events, including enterocolitis. We hypothesized that baseline gut microbiota could predict ipilimumab anti-tumor response and/or intestinal toxicity.Twenty-six patients with metastatic melanoma treated with ipilimumab were prospectively enrolled. Fecal microbiota composition was assessed using 16S rRNA gene sequencing at baseline and before each ipilimumab infusion. Patients were further clustered based on microbiota patterns. Peripheral blood lymphocytes immunophenotypes were studied in parallel.A distinct baseline gut microbiota composition was associated with both clinical response and colitis. Compared to patients whose baseline microbiota was driven by Bacteroides (Cluster B, n =10), patients whose baseline microbiota was enriched with Faecalibacterium genus and other Firmicutes (Cluster A, n =12) had longer progression-free survival ( p =0.0039) and overall survival ( p =0.051). Most of the baseline colitis-associated phylotypes were related to Firmicutes (e.g., relatives of Faecalibacterium prausnitzii and Gemmiger formicilis ), whereas no colitis-related phylotypes were assigned to Bacteroidetes. A low proportion of peripheral blood regulatory T cells was associated with Cluster A, long-term clinical benefit and colitis. Ipilimumab led to a higher Inducible T-cell COStimulator induction on CD4+ T cells and to a higher increase in serum CD25 in patients who belonged to Faecalibacterium -driven Cluster A.Baseline gut microbiota enriched with Faecalibacterium and other Firmicutes is associated with beneficial clinical response to ipilimumab and more frequent occurrence of ipilimumab-induced colitis

Cancer Immunotherapy with Anti-CTLA-4 Monoclonal Antibodies Induces an Inflammatory Bowel Disease

International audienceTherapeutic monoclonal anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies are associated with immune-mediated enterocolitis. The aim of this study was to provide a detailed description of this entity. We included patients with endoscopic signs of inflammation after anti-CTLA-4 infusions for cancer treatment. Other causes of enterocolitis were excluded. Clinical, biological and endoscopic data were recorded. A single pathologist reviewed endoscopic biopsies and colectomy specimens from 27 patients. Patients with and without enterocolitis after ipilimumab-treated melanoma were compared, to identify clinical factors associated with enterocolitis. Thirty-nine patients with anti-CTLA-4 enterocolitis were included (ipilimumab <n = 37; tremelimumab <n = 2). The most frequent symptom was diarrhoea. Ten patients had extra-intestinal manifestations. Most colonoscopies showed ulcerations involving the rectum and sigmoid, 66% of patients had extensive colitis, 55% had patchy distribution and 20% had ileal inflammation. Endoscopic colonic biopsies showed acute colitis in most patients, while half of the patients had chronic duodenitis. Thirty-five patients received steroids that led to complete clinical remission in 13 patients (37%). Twelve patients required infliximab, of whom 10 (83%) responded. Six patients underwent colectomy (perforation <n = 5; toxic megacolon <n = 1); one of them died postoperatively. Four patients had a persistent enterocolitis at follow-up colonoscopy. Patients with enterocolitis were more frequently prescribed NSAIDs compared with patients without enterocolitis (31 vs 5%, <p = 0.003). Ipilimumab and tremelimumab may induce a severe and extensive form of inflammatory bowel disease. Rapid escalation to infliximab should be advocated in patients who do not respond to steroids. Patients treated with anti-CTLA-4 should be advised to avoid NSAIDs

Genetic divergence in forest trees: understanding the consequences of climate change

Predicted climate change is heading in many respects into untested environmental conditions for trees and to the reshuffling of species distributions. We explore the consequences that these changes are likely to have on population differentiation of adaptive traits. Superimposed on the spatial redistribution of the species, will there be a redistribution of their genetic variation? We base our predictions on a conceptual framework, whose elements are the extant differentiation, and the predicted divergent evolution of populations along purposely chosen altitudinal/latitudinal gradients. We consider simultaneously phenotypic and genetic divergence, but emphasize genetically driven population differentiation. We illustrate phenotypic and genetic patterns of variation with examples from well-studied northern and southern hemisphere tree genera Quercus and Eucalyptus. Most phenotypic traits show very large in situ clinal variation with variation in altitude or latitude. Genetic clines detected in common gardens usually follow the observed in situ phenotypic clines, reflecting cogradient variation. Rare counter gradients have also been detected, where phenotypic and genetic clines exhibit opposing signs. These patterns suggest that plasticity and selection contributed in most cases synergistically to the extant differentiation. We anticipate that microevolutionary processes will be different along environmental gradients. At the leading edge, availability of newly suitable habitats will trigger migration favouring genotypes equipped with colonists attributes. At the rear edges of the distribution, populations will be submitted to strong selective pressures favouring genotypes capable of withstanding drought and heat stress. Central populations will benefit from the plastic response of trees that will temporarily compensate for the maladaptation, until genetic adaptive variation will be restored by gene flow, mutation or recombination. We make predictions about future differentiation along environmental gradients, by highlighting traits that are likely to diverge, the rate at which differentiation will take place, and the role of gene flow and hybridization. We envisage that parallel selection may maintain differentiation at extant levels, whereas divergent selection will promote substantial differentiation for traits facilitating adaptation to contrasting conditions along the environmental gradient. We anticipate that genetic divergence may occur very rapidly and will be enhanced by the multilocus architecture of most adaptive traits