Combining TIGIT blockade with MDSC inhibition hinders breast cancer bone metastasis by activating anti-tumor immunity

Bone is the most common site of breast cancer metastasis. Bone metastasis are incurable and are associated with severe morbidity. Utilizing an immunocompetent mouse model of spontaneous breast cancer bone metastasis, we profiled the immune transcriptome of bone metastatic lesions and peripheral bone marrow at distinct metastatic stages, revealing dynamic changes during the metastatic process. We show that crosstalk between granulocytes and T cells is central to shaping an immunosuppressive microenvironment. Specifically, we identified the PD-1 and TIGIT signaling axes and the pro-inflammatory cytokine IL-1b as central players in the interactions between granulocytes and T cells. Targeting these pathways in vivo resulted in attenuated bone metastasis and improved survival, by reactivating anti-tumor immunity. Analysis of patient samples revealed that TIGIT and IL-1b are prominent in human bone metastasis. Our findings suggest that co-targeting immunosuppressive granulocytes and dysfunctional T cells may be a promising novel therapeutic strategy to inhibit bone metastasis. Granulocytes, T helper, T cytotoxic and T regulatory cells were isolated by cell sorting from normal BM, early-stage metastatic BM and from late metastatic stage of mice as described above. At late metastatic stage, two distinct sites were analyzed: the peripheral BM and the bone metastatic core of the same mouse. MARS-seq protocol was used to generate libraries. MARS-seq libraries were sequenced using Illumina NovaSeq 6000.