Intratumoral CD4+ T lymphodepletion sensitizes poorly immunogenic melanomas to immunotherapy with an OX40 agonist.

Previous studies have shown that the antitumor effects of OX40 agonists depend on the immunogenicity of the tumor and that poorly immunogenic tumors such as B16F10 melanomas do not respond to OX40 agonist treatment. In this study, we have shown that intratumoral CD4+ T lymphodepletion sensitized poorly immunogenic B16F10 melanomas to immunotherapy with an OX40 agonist. CD4+ T lymphodepletion dramatically altered the tumor immune microenvironment, making it more susceptible to the antitumor effects of an OX40 agonist by enhancing the accumulation of CD8+ T cells and natural killer (NK) cells in tumor tissue. However, unexpectedly, the number of CD11b+ Gr-1(+) myeloid-derived suppressor cells (MDSCs) within tumor tissues also significantly increased as a result of CD4+ T lymphodepletion. As a countermeasure against CD8+ T-cell accumulation, CCR2-positive CD11b+ Gr-1(int) (monocytic) MDSCs predominantly increased. Treatment with an OX40 agonist under CD4+ T lymphodepletion neither reduced MDSCs nor increased CD8+ T cells and NK cells, but further enhanced the expression of cytotoxic molecules from tumor-infiltrating effector cells. Our results suggest that combined immunotherapy using both an OX40 agonist and CD4+ T lymphodepletion could be a promising therapeutic strategy for poorly immunogenic tumors and might be more effective if further combined with a therapeutic strategy targeting MDSCs.