Intratumoral CD4+ cell depletion sensitizes poorly immunogenic melanomas to immunotherapy with an OX40 agonist

Abstract

OX40 which belongs to the TNF receptor superfamily and is expressed by activated T cells, have potent antitumor activities in preclinical models. However, 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 administration of an anti-CD4 mAb (for CD4+ cell depletion) sensitized poorly immunogenic B16F10 melanomas to immunotherapy with an OX40 agonist. CD4+ cell depletion markedly enhanced the infiltrations of both CD8+ T cells and natural killer (NK) cells into tumor tissues. Cytokines with antitumor activities, such as IFN-γ, TNF-α, IL-2, and IL-12, were significantly upregulated by CD4+ cell depletion. However, unexpectedly, the number of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) within tumor tissues also significantly increased as a result of CD4+ cell depletion. As a countermeasure against CD8+ T cell accumulation, CCR2-positive CD11b+Gr-1int (monocytic) MDSCs predominantly increased. Treatment with an OX40 agonist under CD4+ cell depletion 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+ cell depletion in situ could be a promising therapeutic strategy for poorly immunogenic tumors and might be more effective if further combined with a therapeutic strategy targeting MDSCs.