Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma
Abstract Background In the myeloid compartment of the tumor microenvironment, CD244 signaling has been implicated in immunosuppressive phenotype of monocytes. However, the precise molecular mechanism and contribution of CD244 to tumor immunity in monocytes/macrophages remains elusive due to the co-e...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-024-01936-w |
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| author | Jeongsoo Kim Tae-Jin Kim Sehyun Chae Hyojeong Ha Yejin Park Sunghee Park Chul Joo Yoon Seon Ah Lim Hyemin Lee Jiyoung Kim Jungwon Kim Kyungtaek Im Kyunghye Lee Jeongmin Kim Daham Kim Eunju Lee Min Hwa Shin Serk In Park Inmoo Rhee Keehoon Jung Jeewon Lee Keun Hwa Lee Daehee Hwang Kyung-Mi Lee |
| author_facet | Jeongsoo Kim Tae-Jin Kim Sehyun Chae Hyojeong Ha Yejin Park Sunghee Park Chul Joo Yoon Seon Ah Lim Hyemin Lee Jiyoung Kim Jungwon Kim Kyungtaek Im Kyunghye Lee Jeongmin Kim Daham Kim Eunju Lee Min Hwa Shin Serk In Park Inmoo Rhee Keehoon Jung Jeewon Lee Keun Hwa Lee Daehee Hwang Kyung-Mi Lee |
| author_sort | Jeongsoo Kim |
| collection | DOAJ |
| description | Abstract Background In the myeloid compartment of the tumor microenvironment, CD244 signaling has been implicated in immunosuppressive phenotype of monocytes. However, the precise molecular mechanism and contribution of CD244 to tumor immunity in monocytes/macrophages remains elusive due to the co-existing lymphoid cells expressing CD244. Methods To directly assess the role of CD244 in tumor-associated macrophages, monocyte-lineage-specific CD244-deficient mice were generated using cre-lox recombination and challenged with B16F10 melanoma. The phenotype and function of tumor-infiltrating macrophages along with antigen-specific CD8 T cells were analyzed by flow cytometry and single cell RNA sequencing data analysis, and the molecular mechanism underlying anti-tumorigenic macrophage differentiation, antigen presentation, phagocytosis was investigated ex vivo. Finally, the clinical feasibility of CD244-negative monocytes as a therapeutic modality in melanoma was confirmed by adoptive transfer experiments. Results CD244fl/flLysMcre mice demonstrated a significant reduction in tumor volume (61% relative to that of the CD244fl/fl control group) 14 days after tumor implantation. Within tumor mass, CD244fl/flLysMcre mice also showed higher percentages of Ly6Clow macrophages, along with elevated gp100+IFN-γ+ CD8 T cells. Flow cytometry and RNA sequencing data demonstrated that ER stress resulted in increased CD244 expression on monocytes. This, in turn, impeded the generation of anti-tumorigenic Ly6Clow macrophages, phagocytosis and MHC-I antigen presentation by suppressing autophagy pathways. Combining anti-PD-L1 antibody with CD244−/− bone marrow-derived macrophages markedly improved tumor rejection compared to the anti-PD-L1 antibody alone or in combination with wild-type macrophages. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset revealed close association between CD244 and the inhibition of macrophage maturation and function. Furthermore, the presence of CD244-negative monocytes/macrophages significantly increased patient survival in primary and metastatic tumors. Conclusion Our study highlights the novel role of CD244 on monocytes/macrophages in restraining anti-tumorigenic macrophage generation and tumor antigen-specific T cell response in melanoma. Importantly, our findings suggest that CD244-deficient macrophages could potentially be used as a therapeutic agent in combination with immune checkpoint inhibitors. Furthermore, CD244 expression in monocyte-lineage cells serve as a prognostic marker in cancer patients. |
| first_indexed | 2024-03-07T15:17:19Z |
| format | Article |
| id | doaj.art-b9d69d09111a49bdb32d80e3ebb65c32 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-03-07T15:17:19Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-b9d69d09111a49bdb32d80e3ebb65c322024-03-05T17:52:53ZengBMCMolecular Cancer1476-45982024-02-0123112110.1186/s12943-024-01936-wTargeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanomaJeongsoo Kim0Tae-Jin Kim1Sehyun Chae2Hyojeong Ha3Yejin Park4Sunghee Park5Chul Joo Yoon6Seon Ah Lim7Hyemin Lee8Jiyoung Kim9Jungwon Kim10Kyungtaek Im11Kyunghye Lee12Jeongmin Kim13Daham Kim14Eunju Lee15Min Hwa Shin16Serk In Park17Inmoo Rhee18Keehoon Jung19Jeewon Lee20Keun Hwa Lee21Daehee Hwang22Kyung-Mi Lee23Department of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDivision of Chemical Engineering and Bioengineering, College of Art, Culture and Engineering, Kangwon National UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Chemical and Biological Engineering, College of Engineering, Korea UniversityDepartment of Life Science, Ewha Womans UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityDepartment of Integrative Bioscience and Biotechnology, Sejong UniversityDepartment of Biomedical Sciences, Department of Anatomy and Cell Biology, Seoul National University College of MedicineDepartment of Chemical and Biological Engineering, College of Engineering, Korea UniversityDepartment of Microbiology, College of Medicine, Hanyang UniversitySchool of Biological Sciences, Seoul National UniversityDepartment of Biochemistry and Molecular biology, College of Medicine, Korea UniversityAbstract Background In the myeloid compartment of the tumor microenvironment, CD244 signaling has been implicated in immunosuppressive phenotype of monocytes. However, the precise molecular mechanism and contribution of CD244 to tumor immunity in monocytes/macrophages remains elusive due to the co-existing lymphoid cells expressing CD244. Methods To directly assess the role of CD244 in tumor-associated macrophages, monocyte-lineage-specific CD244-deficient mice were generated using cre-lox recombination and challenged with B16F10 melanoma. The phenotype and function of tumor-infiltrating macrophages along with antigen-specific CD8 T cells were analyzed by flow cytometry and single cell RNA sequencing data analysis, and the molecular mechanism underlying anti-tumorigenic macrophage differentiation, antigen presentation, phagocytosis was investigated ex vivo. Finally, the clinical feasibility of CD244-negative monocytes as a therapeutic modality in melanoma was confirmed by adoptive transfer experiments. Results CD244fl/flLysMcre mice demonstrated a significant reduction in tumor volume (61% relative to that of the CD244fl/fl control group) 14 days after tumor implantation. Within tumor mass, CD244fl/flLysMcre mice also showed higher percentages of Ly6Clow macrophages, along with elevated gp100+IFN-γ+ CD8 T cells. Flow cytometry and RNA sequencing data demonstrated that ER stress resulted in increased CD244 expression on monocytes. This, in turn, impeded the generation of anti-tumorigenic Ly6Clow macrophages, phagocytosis and MHC-I antigen presentation by suppressing autophagy pathways. Combining anti-PD-L1 antibody with CD244−/− bone marrow-derived macrophages markedly improved tumor rejection compared to the anti-PD-L1 antibody alone or in combination with wild-type macrophages. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset revealed close association between CD244 and the inhibition of macrophage maturation and function. Furthermore, the presence of CD244-negative monocytes/macrophages significantly increased patient survival in primary and metastatic tumors. Conclusion Our study highlights the novel role of CD244 on monocytes/macrophages in restraining anti-tumorigenic macrophage generation and tumor antigen-specific T cell response in melanoma. Importantly, our findings suggest that CD244-deficient macrophages could potentially be used as a therapeutic agent in combination with immune checkpoint inhibitors. Furthermore, CD244 expression in monocyte-lineage cells serve as a prognostic marker in cancer patients.https://doi.org/10.1186/s12943-024-01936-wCD244MacrophagesDifferentiationMacrophage-based cell therapyMelanomaImmune checkpoint blockade |
| spellingShingle | Jeongsoo Kim Tae-Jin Kim Sehyun Chae Hyojeong Ha Yejin Park Sunghee Park Chul Joo Yoon Seon Ah Lim Hyemin Lee Jiyoung Kim Jungwon Kim Kyungtaek Im Kyunghye Lee Jeongmin Kim Daham Kim Eunju Lee Min Hwa Shin Serk In Park Inmoo Rhee Keehoon Jung Jeewon Lee Keun Hwa Lee Daehee Hwang Kyung-Mi Lee Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma Molecular Cancer CD244 Macrophages Differentiation Macrophage-based cell therapy Melanoma Immune checkpoint blockade |
| title | Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma |
| title_full | Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma |
| title_fullStr | Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma |
| title_full_unstemmed | Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma |
| title_short | Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma |
| title_sort | targeted deletion of cd244 on monocytes promotes differentiation into anti tumorigenic macrophages and potentiates pd l1 blockade in melanoma |
| topic | CD244 Macrophages Differentiation Macrophage-based cell therapy Melanoma Immune checkpoint blockade |
| url | https://doi.org/10.1186/s12943-024-01936-w |
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