The microbiome restrains melanoma bone growth by promoting intestinal NK and Th1 cell homing to bone

• Type of Material: Article
• Authors: Subhashis Pal, Emory University; Daniel Perrien, Emory University; Tetsuya Yumoto, Emory University; Roberta Faccio, Washington University in St. Louis; Andreea Stoica, Emory University; Jonathan Adams, Emory University; Craig Coopersmith, Emory University; Rheinallt Jones, Emory University; M. Neale Weitzmann, Emory University; Roberto Pacifici, Emory University
• Language: English
• Date: 2022-06-15
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Pal et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI157340
• Title of Journal or Parent Work: JOURNAL OF CLINICAL INVESTIGATION
• Volume: 132
• Issue: 12
• Grant/Funding Information: This study was supported by grants from the National Institutes of Health (DK112946, DK119229, DK124821, and RR028009 to RP; AG062334, AR068157, AR070091, and AR079298 to MNW; GM072808 and GM095442 to CMC). MNW was also supported by a grant from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (5I01BX000105).
• Keywords: Life Sciences & Biomedicine; REQUIRES; GUT MICROBIOTA; Medicine, Research & Experimental; NATURAL-KILLER-CELLS; IN-VIVO; THERAPY; T-CELLS; ANABOLIC ACTIVITY; Science & Technology; BAF312 SIPONIMOD; Research & Experimental Medicine; TRAFFICKING; IFN-GAMMA
• Research Categories: Biology, Anatomy; Biology, Cell; Biology, Genetics

Abstract

Bone metastases are frequent complications of malignant melanoma leading to reduced quality of life and significant morbidity. Regulation of immune cells by the gut microbiome influences cancer progression, but the role of the microbiome in tumor growth in bone is unknown. Using intracardiac or intratibial injections of B16-F10 melanoma cells into mice, we showed that gut microbiome depletion by broad-spectrum antibiotics accelerated intraosseous tumor growth and osteolysis. Microbiome depletion blunted melanoma-induced expansion of intestinal NK cells and Th1 cells and their migration from the gut to tumor-bearing bones. Demonstrating the functional relevance of immune cell trafficking from the gut to the bone marrow (BM) in bone metastasis, blockade of S1P-mediated intestinal egress of NK and Th1 cells, or inhibition of their CXCR3/CXCL9-mediated influx into the BM, prevented the expansion of BM NK and Th1 cells and accelerated tumor growth and osteolysis. Using a mouse model, this study revealed mechanisms of microbiota-mediated gut-bone crosstalk that are relevant to the immunological restraint of melanoma metastasis and tumor growth in bone. Microbiome modifications induced by antibiotics might have negative clinical consequences in patients with melanoma.