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Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.

ABSTRACT: Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

SUBMITTER: Gopalakrishnan V

PROVIDER: S-EPMC5827966 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.

Gopalakrishnan V V Spencer C N CN Nezi L L Reuben A A Andrews M C MC Karpinets T V TV Prieto P A PA Vicente D D Hoffman K K Wei S C SC Cogdill A P AP Zhao L L Hudgens C W CW Hutchinson D S DS Manzo T T Petaccia de Macedo M M Cotechini T T Kumar T T Chen W S WS Reddy S M SM Szczepaniak Sloane R R Galloway-Pena J J Jiang H H Chen P L PL Shpall E J EJ Rezvani K K Alousi A M AM Chemaly R F RF Shelburne S S Vence L M LM Okhuysen P C PC Jensen V B VB Swennes A G AG McAllister F F Marcelo Riquelme Sanchez E E Zhang Y Y Le Chatelier E E Zitvogel L L Pons N N Austin-Breneman J L JL Haydu L E LE Burton E M EM Gardner J M JM Sirmans E E Hu J J Lazar A J AJ Tsujikawa T T Diab A A Tawbi H H Glitza I C IC Hwu W J WJ Patel S P SP Woodman S E SE Amaria R N RN Davies M A MA Gershenwald J E JE Hwu P P Lee J E JE Zhang J J Coussens L M LM Cooper Z A ZA Futreal P A PA Daniel C R CR Ajami N J NJ Petrosino J F JF Tetzlaff M T MT Sharma P P Allison J P JP Jenq R R RR Wargo J A JA

Science (New York, N.Y.) 20171102 6371

Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (<i>n</i> = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patien ...[more]

PMID: 29097493

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Project description:IntroductionImmunotherapy with checkpoint inhibitors is an efficient treatment for metastatic melanoma. Development of vitiligo upon immunotherapy represents a specific immune-related adverse event (irAE) diagnosed in 15% of patients and associated with a positive clinical response. Therefore, a detailed characterization of immune cells during vitiligo onset in melanoma patients would give insight into the immune mechanisms mediating both the irAE and the anti-tumor response.MethodsTo better understand these aspects, we analyzed T cell subsets from peripheral blood of metastatic melanoma patients undergoing treatment with anti-programmed cell death protein (PD)-1 antibodies. To deeply characterize the antitumoral T cell response concomitant to vitiligo onset, we analyzed T cell content in skin biopsies collected from melanoma patients who developed vitiligo. Moreover, to further characterize T cells in vitiligo skin lesion of melanoma patients, we sequenced T cell receptor (TCR) of cells derived from biopsies of vitiligo and primary melanoma of the same patient.Results and discussionStratification of patients for developing or not developing vitiligo during anti-PD-1 therapy revealed an association between blood reduction of CD8-mucosal associated invariant T (MAIT), T helper (h) 17, natural killer (NK) CD56bright, and T regulatory (T-reg) cells and vitiligo onset. Consistently with the observed blood reduction of Th17 cells in melanoma patients developing vitiligo during immunotherapy, we found high amount of IL-17A expressing cells in the vitiligo skin biopsy, suggesting a possible migration of Th17 cells from the blood into the autoimmune lesion. Interestingly, except for a few cases, we found different TCR sequences between vitiligo and primary melanoma lesions. In contrast, shared TCR sequences were identified between vitiligo and metastatic tissues of the same patient. These data indicate that T cell response against normal melanocytes, which is involved in vitiligo onset, is not typically mediated by reactivation of specific T cell clones infiltrating primary melanoma but may be elicited by T cell clones targeting metastatic tissues. Altogether, our data indicate that anti-PD-1 therapy induces a de novo immune response, stimulated by the presence of metastatic cells, and composed of different T cell subtypes, which may trigger the development of vitiligo and the response against metastatic tumor.

Project description:BackgroundImmune checkpoint inhibition (ICI) has changed the melanoma treatment spectrum. Few studies have examined the characteristics and long-term outcomes of patients achieving complete response (CR) under ICI.Materials and methodsWe evaluated patients with unresectable stage IV melanoma treated with first-line ICI. The characteristics of those achieving CR were compared with those not achieving CR. Progression-free survival (PFS) and overall survival (OS) were assessed. Late-onset toxicities, response to second-line treatment, the prognostic value of clinicopathologic features, and blood markers were examined.ResultsA total of 265 patients were included; 41 (15.5%) achieved CR, while 224 (84.5%) had progressive disease, stable disease, or partial response. At the therapy start, those who had CR were more likely to be older than 65 years of age (p = 0.013), have a platelet-to-lymphocyte ratio below 213 (p = 0.036), and have lower lactate dehydrogenase levels (p = 0.008) than those not achieving a CR. For those who discontinued therapy after CR, the median follow-up time after CR was 56 months (interquartile range [IQR] 52-58) and the median time from CR to therapy end was 10 months (IQR 1-17). Five-year PFS after CR was 79% and 5-year OS was 83%. Most complete responders had a normalization of S100 at the time of CR (p < 0.001). In simple Cox regression analysis, age below 77 years at CR (p = 0.04) was associated with better prognosis after CR. Eight patients received second-line ICI; disease control was seen in 63%. Late immune-related toxicities occurred in 25% of patients, most being cutaneous immune-related toxicities.ConclusionsResponse, according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, is, until now, the most important prognostic factor, and CR is a valid surrogate marker for long-term survival in patients treated with ICI. Our results highlight the importance of investigating the optimal therapy duration in complete responders.

Dataset Information

Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.

Publications

Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.

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