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Targeting the CCL2/CCR2 Axis in Cancer Immunotherapy: One Stone, Three Birds?
Liyang Fei1, Xiaochen Ren1, Haijia Yu1
1Department of Drug Discovery, Shanghai Huaota Biopharm, Shanghai, China.
Abstract:
CCR2 is predominantly expressed by monocytes/macrophages with strong proinflammatory functions, prompting the development of CCR2 antagonists to dampen unwanted immune responses in inflammatory and autoimmune diseases. Paradoxically, CCR2-expressing monocytes/macrophages, particularly in tumor microenvironments, can be strongly immunosuppressive. Thus, targeting the recruitment of immunosuppressive monocytes/macrophages to tumors by CCR2 antagonism has recently been investigated as a strategy to modify the tumor microenvironment and enhance anti-tumor immunity. We present here that beneficial effects of CCR2 antagonism in the tumor setting extend beyond blocking chemotaxis of suppressive myeloid cells. Signaling within the CCL2/CCR2 axis shows underappreciated effects on myeloid cell survival and function polarization. Apart from myeloid cells, T cells are also known to express CCR2. Nevertheless, tissue homing of Treg cells among T cell populations is preferentially affected by CCR2 deficiency. Further, CCR2 signaling also directly enhances Treg functional potency. Thus, although Tregs are not the sole type of T cells expressing CCR2, the net outcome of CCR2 antagonism in T cells favors the anti-tumor arm of immune responses. Finally, the CCL2/CCR2 axis directly contributes to survival/growth and invasion/metastasis of many types of tumors bearing CCR2. Together, CCR2 links to two main types of suppressive immune cells by multiple mechanisms. Such a CCR2-assoicated immunosuppressive network is further entangled with paracrine and autocrine CCR2 signaling of tumor cells. Strategies to target CCL2/CCR2 axis as cancer therapy in the view of three types of CCR2-expessing cells in tumor microenvironment are discussed.
Insights
Targeting chemokine receptor 2 (CCR2) with antagonists offers a novel cancer therapy. Blocking CCR2 not only reduces immunosuppressive myeloid cells but also enhances anti-tumor immunity by affecting T regulatory cells and tumor growth.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Chemokine receptor 2 (CCR2) is primarily found on monocytes/macrophages, known for pro-inflammatory roles, leading to CCR2 antagonist development for inflammatory diseases.
- Paradoxically, CCR2-expressing cells in tumors can be immunosuppressive, making CCR2 antagonism a potential strategy to enhance anti-tumor immunity.
- The CCL2/CCR2 axis influences myeloid cell survival and polarization, and also affects T cell tissue homing and regulatory T cell (Treg) function.
Purpose of the Study:
- To investigate the multifaceted roles of the CCL2/CCR2 axis in the tumor microenvironment.
- To explore how CCR2 antagonism impacts immunosuppressive cells, anti-tumor immunity, and tumor progression.
- To discuss therapeutic strategies targeting the CCL2/CCR2 axis in cancer.
Main Methods:
- Analysis of CCR2 expression and function in monocytes, macrophages, T cells (including Tregs), and tumor cells.
- Investigating the effects of CCR2 antagonism on immune cell recruitment, survival, polarization, and function within the tumor microenvironment.
- Evaluating the impact of CCR2 signaling on tumor cell survival, growth, invasion, and metastasis.
Main Results:
- CCR2 antagonism extends beyond blocking suppressive myeloid cell recruitment, influencing myeloid cell survival and polarization.
- CCR2 signaling directly impacts T regulatory cell (Treg) tissue homing and functional potency, favoring anti-tumor immune responses.
- The CCL2/CCR2 axis promotes the survival, growth, invasion, and metastasis of CCR2-expressing tumors.
Conclusions:
- CCR2 is a critical link between tumor cells and multiple immunosuppressive immune cell types through various mechanisms.
- The CCL2/CCR2 axis presents a promising therapeutic target in cancer, modulating both immune responses and tumor progression.
- Targeting the CCL2/CCR2 axis offers a comprehensive strategy to enhance anti-tumor immunity and combat cancer metastasis.
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