Differences in tumor microenvironment dictate T helper lineage polarization and response to immune checkpoint therapy

Immune checkpoint therapy (ICT) showed encouraging results in a subset of patients with metastatic castration resistant prostate cancer (mCRPC), but still elicited a sub-optimal response among those with bone metastases. Analysis of patients’ bone marrow samples revealed increased Th17 instead of Th1 subsets following ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increased intra-tumoral Th1 subsets and improved survival. However, ICTfailed to elicit an anti-tumor response in the bone CRPC model despite an increase in the intratumoral CD4+ T cells, which were polarized to Th17 rather than Th1 lineage. Mechanistically, tumors in the bone promoted osteoclast-mediated bone resorption that released TGF-β, which restrained Th1 lineage development. Blocking TGF-β along with ICT increased Th1 subsets and promoted clonal expansion of CD8+ T cells, with subsequent regression of bone CRPC and improved survival