IMMUNE NETWORK

  • 제21권3호
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  • Pages.23.1-23.16
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  • 2021
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  • 1598-2629(pISSN)
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  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
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Enriching CCL3 in the Tumor Microenvironment Facilitates T cell Responses and Improves the Efficacy of Anti-PD-1 Therapy

  • Tae Gun Kang (Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University) ;
  • Hyo Jin Park (Yuhan Corporation, Chemistry & Chemical Biology Team, Yuhan R&D Institute) ;
  • Jihyun Moon (Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University) ;
  • June Hyung Lee (Yuhan Corporation, Biologics Discovery Team) ;
  • Sang-Jun Ha (Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University)
  • 투고 : 2021.05.10
  • 심사 : 2021.06.09
  • 발행 : 2021.06.30
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초록

Chemokines are key factors that influence the migration and maintenance of relevant immune cells into an infected tissue or a tumor microenvironment. Therefore, it is believed that the controlled administration of chemokines in the tumor microenvironment may be an effective immunotherapy against cancer. Previous studies have shown that CCL3, also known as macrophage inflammatory protein 1-alpha, facilitates the recruitment of dendritic cells (DCs) for the presentation of tumor Ags and promotes T cell activation. Here, we investigated the role of CCL3 in regulating the tumor microenvironment using a syngeneic mouse tumor model. We observed that MC38 tumors overexpressing CCL3 (CCL3-OE) showed rapid regression compared with the wild type MC38 tumors. Additionally, these CCL3-OE tumors showed an increase in the proliferative and functional tumor-infiltrating T cells. Furthermore, PD-1 immune checkpoint blockade accelerated tumor regression in the CCL3-OE tumor microenvironment. Next, we generated a modified CCL3 protein for pre-clinical use by fusing recombinant CCL3 (rCCL3) with a non-cytolytic hybrid Fc (HyFc). Administering a controlled dose of rCCL3-HyFc via subcutaneous injections near tumors was effective in tumor regression and improved survival along with activated myeloid cells and augmented T cell responses. Furthermore, combination therapy of rCCL3-HyFc with PD-1 blockade exhibited prominent effect to tumor regression. Collectively, our findings demonstrate that appropriate concentrations of CCL3 in the tumor microenvironment would be an effective adjuvant to promote anti-tumor immune responses, and suggest that administering a long-lasting form of CCL3 in combination with PD-1 blockers can have clinical applications in cancer immunotherapy.

키워드

과제정보

We wish to thank S.W. Lee at POSTECH for providing MC38 cell lines. This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2017R1A5A1014560, 2018R1A2A1A05076997, 2019M3A9B6065221) and by grants from Bridge Biotherapeutics, Inc., Korea.

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