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

• Published in: The Journal of clinical investigation 2022-06, Vol.132 (12), p.1-21
• Main Authors: Pal, Subhashis, Perrien, Daniel S, Yumoto, Tetsuya, Faccio, Roberta, Stoica, Andreea, Adams, Jonathan, Coopersmith, Craig M, Jones, Rheinallt M, Weitzmann, M Neale, Pacifici, Roberto
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Antibiotics; Bacteria; Biomedical research; Bone Biology; Bone cancer; Bone Development; Bone growth; Bone marrow; Bone tumors; CD4 lymphocytes; Chemokines; Complications and side effects; CXCR3 protein; Development and progression; Digestive organs; Digestive system; Drinking water; Estrogens; Gastrointestinal Microbiome; Gastrointestinal tract; Health aspects; Homing behavior; Humans; Intestinal microflora; Intestine; Killer cells; Lymphocytes T; Melanoma; Melanoma, Experimental - pathology; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Microbiomes; Microbiota; Microbiota (Symbiotic organisms); Morbidity; Osteolysis; Physiological aspects; Quality of Life; Risk factors; Skin cancer; Th1 Cells - pathology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI157340

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.