Bone-Metastasis Microenvironment May Explain Immunotherapy Resistance

The use of immune-checkpoint blockade (ICB) is effective in some patients with metastatic castration-resistant prostate cancer (CRPC), but efficacy in patients with bone metastases is limited. In paired pre- and post-treatment primary prostate tumors and bone marrow samples from the same patients, Jiao and colleagues found that anti-CTLA4 (specifically, ipilimumab) treatment caused T_h1 expansion in the prostate tumors, but not in the bone marrow, which instead exhibited an increase in cells of the T_h17 lineage. Treatment with anti-CTLA4 and anti–PD-1 caused tumor regression and improved overall survival in mice injected subcutaneously with prostate-cancer cells but had little effect on prostate-cancer cells injected into the bones despite triggering an expansion of tumor-infiltrating T cells in both models. In the bone CRPC model, the CD4⁺ T-cell population was composed solely of regulatory T cells (Treg) and T_h17 cells, and the population of the latter increased after ICB treatment. Notably, T_h1 effector cells were lacking in the bone CRPC tumors, which may explain the inferior response of these tumors to ICB. Compared with bone marrow from tumor-free femurs, bone marrow from tumor-bearing femurs had increased TGFβ1 levels, which may have resulted from an observed increase in osteoclast-mediated bone resorption. In the mouse bone CRPC model, combination treatment with anti-CTLA4 and anti-TGFβ reduced tumor growth and improved overall survival more than either treatment alone, and the combination treatment resulted in an increase in T_h1 cells and a decrease in Tregs in the tumor-infiltrating T-cell population. Further experiments revealed that the combination treatment caused a clonal expansion of tumor-specific CD8⁺ T cells, most of which exhibited a memory–effector signature. Together, these findings suggest that TGFβ-mediated restriction of development of the T_h1 lineage along with insufficient expansion and activation of CD8⁺ T cells may be responsible for the resistance of CRPC bone metastases to ICB. Additionally, this study demonstrates that combination therapy with ICB and anti-TGFβ may be worth investigating.

Jiao S, Subudhi SK, Aparicio A, Ge Z, Guan B, Miura Y, et al. Differences in tumor microenvironment dictate T helper lineage polarization and response to immune checkpoint therapy. Cell 2019;179:1177–90.e13.

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