Blockade of CCR1 induces a phenotypic shift in macrophages and triggers a favorable antilymphoma activity

by Selleckchem | Dec 28 2023

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 monocytes (Mo) and macrophages (MΦ), and CCR1 pharmacological inhibition or CCR1 siRNA abolished lymphoma-mediated Mo/MΦ migration in a chemotaxis assay. The deficiency of host CCR1 (CCR1 KO) was associated with decreased infiltration of peritoneal-MΦ compared with WT-CCR1. Functional studies indicated that the genetic depletion of CCR1 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 BX-471 significantly reduced FC-muMCL1 mouse tumors in the syngeneic MCL model by the depletion of M2-TAMs and 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.

Comments:

This is an intriguing study that sheds light on the role of CCR1 in the tumor microenvironment of B-cell lymphoma, particularly mantle cell lymphoma (MCL). The findings suggest that CCR1 plays a crucial role in regulating the behavior and polarization of tumor-associated macrophages (TAMs), influencing the immunosuppressive environment within the tumor.

The research indicates that inhibiting CCR1, either through pharmacological means or genetic depletion, hinders the migration of monocytes and macrophages, leading to decreased infiltration of protumor M2-like macrophages in the tumor microenvironment. Instead, this inhibition promotes the development of a more immunogenic MHCII+/TNFα+ phenotype in macrophages, which can potentially enhance antitumor immune responses.

The study also uncovers a mechanistic link between IL-10 produced by protumor M2-like macrophages and the regulation of CCL3 expression, suggesting a positive feedback loop that contributes to the immunosuppressive tumor microenvironment.

Moreover, the therapeutic targeting of CCR1 using the CCR1 antagonist BX-471 in an in vivo model of MCL resulted in reduced tumor growth by depleting M2-like TAMs and increasing the infiltration of cytotoxic CD8+ T cells. This implies that manipulating CCR1 could serve as a promising strategy to alter macrophage behavior within the tumor microenvironment, potentially leading to improved clinical outcomes for lymphoma patients.

Overall, the study establishes a significant role for CCR1 in modulating macrophage polarization and shaping the tumor microenvironment in B-cell lymphoma, suggesting that CCR1 inhibition could be a viable therapeutic approach to reprogram TAMs and enhance antitumor immunity.