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

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.

Efficient and multiplexed tracking of single cells using whole-body PET/CT

“…Our data further suggest that cells arrested very quickly after injection, within the first minute, likely through passive trapping in capillary beds. Interestingly, prior studies of metastases formation following intracardiac injection mainly reported bone metastases, 24,27,28 even though the musculoskeletal system accounted for only 22% of the cell arrest in our study. This observation suggests that the bone marrow may provide a more supportive niche for the survival and rapid growth of metastatic lesions, as originally postulated in the “seed and soil” hypothesis.…”

NK cells are never alone: crosstalk and communication in tumour microenvironments

“…It has been observed that the growth of melanoma cells in bone triggers the proliferation of intestinal NK and Th1 cells and their homing to tumour-bearing bone to inhibit melanoma bone metastasis. This trigger is microbially dependent, and it is weakened by microbiome depletion, thus increasing the progression of bone metastasis [ 208 ]. Similarly, Yin et al found that Fusobacterium nucleatum promotes CRC liver metastasis by increasing the accumulation of MDSCs and Tregs in the liver of a CRC mouse model and reducing the infiltration of NK cells to inhibit the immune niche of the liver [ 209 ].…”

The crosstalk between the gut microbiota and tumor immunity: Implications for cancer progression and treatment outcomes

“…NK cells are key ILCs mediating tumor immunosurveillance and elimination ( 79 ). The gut microbiota was reported to blunt melanoma bone growth ( 51 ). Gut microbiota depletion by broad-spectrum antibiotics (ATB) promoted intraosseous melanoma growth by blocking melanoma-induced expansion of intestinal NK cells and Th1 cells and their egress from the gut into the bone marrow of tumor-bearing bones.…”