Anti-CTLA4 caused Th1 expansion in primary prostate-cancer tumors, but not bone metastases.

  • Major Finding: Anti-CTLA4 caused Th1 expansion in primary prostate-cancer tumors, but not bone metastases.

  • Concept: Anti-CTLA4 plus anti–TGFβ was more effective in treating bone metastases than either alone in mice.

  • Impact: Bone metastases’ microenvironment may explain their resistance to immune-checkpoint blockade.

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 Th1 expansion in the prostate tumors, but not in the bone marrow, which instead exhibited an increase in cells of the Th17 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 Th17 cells, and the population of the latter increased after ICB treatment. Notably, Th1 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 Th1 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 Th1 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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