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Theranostics 2024; 14(2):843-860. doi:10.7150/thno.88917 This issue Cite

Research Paper

Comprehensive characterization of early-programmed tumor microenvironment by tumor-associated macrophages reveals galectin-1 as an immune modulatory target in breast cancer

Hyewon Chung^1,2, Park Gyu-mi^1,3, Yi Rang Na⁴, Yun-Sang Lee^5,6, Hongyoon Choi^5,6✉, Seung Hyeok Seok^1,3,7✉

1. Macrophage Lab, Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul 110-799, South Korea.
2. Institute of Endemic Diseases, Seoul National University Medical Research Center (SNUMRC), Seoul, Republic of Korea.
3. Department of Biomedical Sciences and Seoul National University College of Medicine, Seoul, Republic of Korea.
4. Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, South Korea.
5. Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
6. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
7. Cancer Research Institute, Seoul National University, Seoul, South Korea.

✉ Corresponding authors: Hongyoon Choi, M.D., Ph.D.; Department of Nuclear Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-Gu, Seoul, 03080, Korea, Tel: 82-2-2072-3347, E-mail: chy1000ac.kr. Seung Hyeok Seok, DVM, Ph.D., Professor; Macrophages Laboratory, Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea, E-mail: lamseokac.kr, Tel: +82-2-740-8302; Fax: +82-2-743-0881. More

Abstract

Background: In recent years, there has been considerable interest in the therapeutic targeting of tumor-associated macrophages (TAMs) to modulate the tumor microenvironment (TME), resulting in antitumoral phenotypes. However, key mediators suitable for TAM-mediated remodeling of the TME remain poorly understood.

Methods: In this study, we used single-cell RNA sequencing analyses to analyze the landscape of the TME modulated by TAMs in terms of a protumor microenvironment during early tumor development.

Results: Our data revealed that the depletion of TAMs leads to a decreased epithelial-to-mesenchymal transition (EMT) signature in cancer cells and a distinct transcriptional state characterized by CD8⁺ T cell activation. Moreover, notable alterations in gene expression were observed upon the depletion of TAMs, identifying Galectin-1 (Gal-1) as a crucial molecular factor responsible for the observed effect. Gal-1 inhibition reversed immune suppression via the reinvigoration of CD8⁺ T cells, impairing tumor growth and potentiating immune checkpoint inhibitors in breast tumor models.

Conclusion: These results provide comprehensive insights into TAM-mediated early tumor microenvironments and reveal immune evasion mechanisms that can be targeted by Gal-1 to induce antitumor immune responses.

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