한빛사논문
- 조회484
Jeongsoo Kim 1,†, Tae-Jin Kim 1,2,†, Sehyun Chae 3,†, Hyojeong Ha 1, Yejin Park 1, Sunghee Park 1, Chul Joo Yoon 4, Seon Ah Lim 5, Hyemin Lee 1, Jiyoung Kim 1, Jungwon Kim 1, Kyungtaek Im 1, Kyunghye Lee 1, Jeongmin Kim 1, Daham Kim 1,2, Eunju Lee 1,2, Min Hwa Shin 1,10, Serk In Park 1, Inmoo Rhee 6, Keehoon Jung 7, Jeewon Lee 4, Keun Hwa Lee 8,*, Daehee Hwang 9,* and Kyung-Mi Lee 1,*
1Department of Biochemistry and Molecular biology, College of Medicine, Korea University, Seoul 02841, South Korea
2Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, South Korea
3Division of Chemical Engineering and Bioengineering, College of Art, Culture and Engineering, Kangwon National University, Chuncheon 24341, South Korea
4Department of Chemical and Biological Engineering, College of Engineering, Korea University, Seoul 02841, South Korea
5Department of Life Science, Ewha Womans University, Seoul 03760, South Korea
6Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul 05006, South Korea
7Department of Biomedical Sciences, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
8Department of Microbiology, College of Medicine, Hanyang University, Seoul 04763, South Korea
9School of Biological Sciences, Seoul National University, Seoul 08826, South Korea
10Present address: Immune Research Institute, Seegene Medical Foundation, Seoul 04805, South Korea
†Jeongsoo Kim, Tae-Jin Kim and Sehyun Chae contributed equally to this work
*Corresponding authors: correspondence to Keun Hwa Lee, Daehee Hwang or Kyung-Mi Lee
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.
논문정보
- Research article
- 2024년 02월 (BRIC 등록일 2024-03-04)
- 국내 연구진
- 의약학 > 면역의학
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