A Small Molecule CCR2 Antagonist Depletes Tumor Macrophages and Synergizes with Anti–PD-1 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 the support of tumor growth. We hypothesize that blocking monocyte trafficking (through the inhibition of specific chemokine receptors) into skin can positively affect tumor development. Herein, the authors examined 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, the depletion of macrophages was achieved as early as 2 days after tumor initiation in ear TME. Quantitative real-time PCR detected an increase in the levels of immune stimulatory inflammatory cytokines, for example, IFN-g and IL-12, in CCR2i-versus vehicle-treated mice. Within 2 weeks, the tumors from the control groups attained the maximum size, whereas CCR2i-treated mice exhibited much smaller tumor sizes and weights. Immunohistochemistry revealed that CCR2i-treated tumors possessed considerably more CD8þ T cells, which demonstrated their essential role in CCR2i-induced tumor inhibition. Finally, the combination of anti-programmed cell death protein 1 with CCR2i considerably increased the efficacy of tumor eradication related to the activation of IFN-geproducing 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 option for cutaneous T-cell lymphomas.

Serum CCL22 levels decreased in parallel with disease activity in CCR4 ‐positive mycosis fungoides treated with mogamulizumab

“…In addition, bexarotene reduced the production of CCL22 from monocytes‐derived M2 macrophages in vitro, 5 whereas interferon‐α and interferon‐γ did not affect the production of CCL22 6 . In another report, Wu et al 7 reported that a CCR2 antagonist inhibited the recruitment of a TAM precursor and decreased TAM levels in the tumor microenvironment, leading to the suppression of tumor growth in a mouse MBL2/DNFB CTCL model. Moreover, the depletion of TAMs by clodronate‐containing liposomes suppressed tumor growth in a human CTCL xenograft model 8 .…”

“…Since most lymphoma cells in MF express CCR4, which plays crucial roles in the trafficking of CTCL cells to skin, 3 and since MF develops from patch and plaque stages to the tumor stage, 4 it is important for the development of treatments for MF to investigate the tumor microenvironment with a focus on chemokine production 3‐7 . Indeed, as we previously reported, TAMs in the lesional skin of MF produce various chemokines, 5,6 and they may be a target for anti‐CTCL therapy, such as bexarotene 5 and interferons 6 .…”

“…In addition, bexarotene reduced the production of CCL22 from monocytes-derived M2 macrophages in vitro, 5 whereas interferon-α and interferon-γ did not affect the production of CCL22. 6 In another report, Wu et al 7 reported that a CCR2 antagonist inhibited the recruitment of a including CCL22. 6,9 In addition, IL-13 has been reported as a growth factor that regulates the proliferation of CTCL cells in MF.…”

Re-education of the Tumor Microenvironment With Targeted Therapies and Immunotherapies

“…Alternatively, targeting the CCL2/CCR2 axis, a key chemokine pathway involved in macrophage migration to inflammatory sites, to limit their entry into the TME enabled numerical and functional improvement of intratumoral lymphocyte infiltrate ( 26 – 29 ). Wu et al demonstrated improved survival outcomes in cutaneous T-cell lymphoma-bearing mice treated with a CCR2 inhibitor and anti-PD-1 ( 28 ). Collectively, these studies highlight that inhibition of pro-tumor TAMs in the TME reinvigorates the anti-PD-1-driven T cell response.…”

“…Therapeutically altering these immunomodulatory components may promote anti-tumor immunity either alone or synergize with FDA-approved immune checkpoint inhibition. enabled numerical and functional improvement of intratumoral lymphocyte infiltrate (26)(27)(28)(29). Wu et al demonstrated improved survival outcomes in cutaneous T-cell lymphoma-bearing mice treated with a CCR2 inhibitor and anti-PD-1 (28).…”