Targeting the CCL2/CCR2 Axis in Cancer Immunotherapy: One Stone, Three Birds?
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 micro...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.771210/full |
| _version_ | 1819117591454547968 |
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| author | Liyang Fei Xiaochen Ren Haijia Yu Yifan Zhan |
| author_facet | Liyang Fei Xiaochen Ren Haijia Yu Yifan Zhan |
| author_sort | Liyang Fei |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T05:35:25Z |
| format | Article |
| id | doaj.art-44f816e4bb85407aa777748024a06291 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T05:35:25Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-44f816e4bb85407aa777748024a062912022-12-21T18:37:20ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-11-011210.3389/fimmu.2021.771210771210Targeting the CCL2/CCR2 Axis in Cancer Immunotherapy: One Stone, Three Birds?Liyang FeiXiaochen RenHaijia YuYifan ZhanCCR2 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.771210/fullCCL2CCR2cancer immunotherapymacrophagesT regulatory cells |
| spellingShingle | Liyang Fei Xiaochen Ren Haijia Yu Yifan Zhan Targeting the CCL2/CCR2 Axis in Cancer Immunotherapy: One Stone, Three Birds? Frontiers in Immunology CCL2 CCR2 cancer immunotherapy macrophages T regulatory cells |
| title | Targeting the CCL2/CCR2 Axis in Cancer Immunotherapy: One Stone, Three Birds? |
| title_full | Targeting the CCL2/CCR2 Axis in Cancer Immunotherapy: One Stone, Three Birds? |
| title_fullStr | Targeting the CCL2/CCR2 Axis in Cancer Immunotherapy: One Stone, Three Birds? |
| title_full_unstemmed | Targeting the CCL2/CCR2 Axis in Cancer Immunotherapy: One Stone, Three Birds? |
| title_short | Targeting the CCL2/CCR2 Axis in Cancer Immunotherapy: One Stone, Three Birds? |
| title_sort | targeting the ccl2 ccr2 axis in cancer immunotherapy one stone three birds |
| topic | CCL2 CCR2 cancer immunotherapy macrophages T regulatory cells |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.771210/full |
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