Blockade of CCR1 induces a phenotypic shift in macrophages and triggers a favorable antilymphoma activity
Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME), play an important role in tumor growth and progression. TAMs have been involved in producing immunosuppressive TME via various factors; however, the underlying mechanisms remain unclear in B-cell lymphoma including mantle cell lymphoma (MCL). We identified that chemokine receptor-1 (CCR1) is highly expressed on monocyte (Mo) and macrophages (MΦ), and CCR1 pharmacological inhibition or CCR1 siRNA abolished lymphoma-mediated Mo/MΦ migration in a chemotaxis assay. Deficiency of host CCR1 (CCR1 KO) was associated with decreased infiltration of peritoneal-MΦ compared with WT-CCR1. Functional studies indicated that CCR1 genetic depletion or treatment inhibited protumor MΦ (M2-like) phenotype by decreasing CD206 and IL-10 expression. Moreover, CCR1 depletion reprogrammed MΦ toward an MHCII+/TNFα+ immunogenic phenotype. Mechanistically, protumor MΦ driven IL-10 provides a positive feedback loop to tumor-CCL3 by regulating the CCL3 promoter via STAT1 signaling. Therapeutic in-vivo targeting of CCR1 with CCR1 antagonist BX471 significantly reduced FC-muMCL-1 mouse tumors in the syngeneic MCL model by depletion of M2-TAMs and by increased infiltration of cytotoxic CD8+ T cells. Our study established that CCR1 exerts a pivotal role in macrophage programming, thus shaping protumor TME and lymphoma progression. CCR1 inhibition through CCR1 antagonists may be a promising therapeutic strategy to reprogram macrophages in lymphoma-TME and achieve better clinical outcomes in patients.
Le, Kang; Sun, Jing; Ghaemmaghami, Javid; Smith, Mitchell R.; Ip, W K.; Phillips, Tycel Jovelle; and Gupta, Mamta, "Blockade of CCR1 induces a phenotypic shift in macrophages and triggers a favorable antilymphoma activity" (2023). GW Authored Works. Paper 2282.
Biochemistry and Molecular Medicine