A small molecule CCR2 antagonist depletes tumor macrophages and synergizes with anti-PD1 in a murine model of cutaneous T cell lymphoma (CTCL)

Abstract Tumor-associated macrophages (TAMs) recruited from blood monocytes are key in establishing an immunosuppressive tumor microenvironment (TME) for supporting tumor growth. We hypothesize that blocking monocyte trafficking (through inhibition of specific chemokine receptors) into skin can influence tumor development. Herein, we examine the effects of oral administration of a small molecule inhibitor for CCR2, CCR2i, which blocks CCR2-mediated chemotaxis of monocytes in a syngeneic mouse T cell lymphoma in skin. Following CCR2i administration, depletion of macrophages was achieved as early as two days after tumor initiation in ear TME. Quantitative RT-PCR detected increases in the levels of immune stimulatory inflammatory cytokines, e.g. IFN-γ and IL-12, in CCR2i- vs. vehicle-treated mice. Within two weeks the tumors from control groups attained the maximum size, while CCR2i-treated mice exhibited much smaller tumor sizes and weights. Immunohistochemistry revealed CCR2i-treated tumors possessed significantly more CD8+ T cells, which demonstrated their essential role in CCR2i-induced tumor inhibition. Lastly, combining anti-PD1 with CCR2i significantly increased the efficacy of tumor eradication related to activation of IFN-γ-producing CD8-T cells. Our findings provide strong evidence that the CCR2i, particularly in combination with an immune checkpoint inhibitor, reduces tumor growth and is a potential future treatment of cutaneous T cell lymphomas.