Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy

Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients' bone marrow samples revealed increased T(h)17 instead of T(h)1 subsets after 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 increases intra-tumoral T(h)1 subsets and improves survival. However, ICT fails to elicit an anti-tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to T(h)17 rather than T(h)1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-8, which restrains T(h)1 lineage development. Blocking TGF-beta along with ICT increases T(h)1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.