한빛사논문
- 조회194
Keun Bon Ku1,2, Chae Won Kim3,4, Yumin Kim3, Byeong Hoon Kang1,3, Jeongwoo La1,3, In Kang1,3, Won Hyung Park1,3, Stephen Ahn5, Sung Ki Lee6 and Heung Kyu Lee3,7
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
2Center for Infectious Disease Vaccine and Diagnosis Innovation, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
3Laboratory of Host Defenses, Department of Biological Sciences, KAIST, Daejeon 34141, Republic of Korea
4Life Science Institute, KAIST, Daejeon 34141, Republic of Korea
5Department of Neurosurgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
6Department of Obstetrics and Gynecology, College of Medicine, Myunggok Medical Research Center, Konyang University, Daejeon 35365, Republic of Korea
7KAIST Institute of Health Science and Technology, KAIST, Daejeon 34141, Republic of Korea
Correspondence to Professor Heung Kyu Lee
Abstract
Background Certain cancers present challenges for treatment because they are resistant to immune checkpoint blockade (ICB), attributed to low tumor mutational burden and the absence of T cell-inflamed features. Among these, glioblastoma (GBM) is notoriously resistant to ICB. To overcome this resistance, the identification of T cells with heightened stemness marked by T-cell factor 1 (TCF1) expression has gained attention. Several studies have explored ways to preserve stem-like T cells and prevent terminal exhaustion. In this study, we investigate a target that triggers stem-like properties in CD8 T cells to enhance the response to ICB in a murine GBM model.
Methods Using Fcgr2b−/− mice and a murine GL261 GBM model, we confirmed the efficacy of anti-programmed cell death protein-1 (PD-1) immunotherapy, observing improved survival. Analysis of immune cells using fluorescence-activated cell sorting and single-cell RNA sequencing delineated distinct subsets of tumor-infiltrating CD8 T cells in Fcgr2b−/− mice. The crucial role of the stem-like feature in the response to anti-PD-1 treatment for reinvigorating CD8 T cells was analyzed. Adoptive transfer of OT-I cells into OVA-expressing GL261 models and CD8 T cell depletion in Fcgr2b−/− mice confirmed the significance of Fcgr2b−/− CD8 T cells in enhancing the antitumor response. Last, S1P1 inhibitor treatment confirmed that the main source of tumor antigen-specific Fcgr2b−/− CD8 T cells is the tumor-draining lymph nodes (TdLNs).
Results In a murine GBM model, anti-PD-1 monotherapy and single-Fc fragment of IgG receptor IIb (FcγRIIB) deletion exhibit limited efficacy. However, their combination substantially improves survival by enhancing cytotoxicity and proliferative capacity in tumor-infiltrating Fcgr2b−/− CD8 T cells. The improved response to anti-PD-1 treatment is associated with the tumor-specific memory T cells (Ttsms) exhibiting high stemness characteristics within the tumor microenvironment (TME). Ttsms in the TdLN thrives in a protective environment, maintaining stem-like characteristics and serving as a secure source for tumor infiltration. This underscores the significance of FcγRIIB ablation in triggering Ttsms and enhancing ICB therapy against GBM.
Conclusions Deletion of FcγRIIB on CD8 T cells leads to the generation of a Ttsms, which is localized in TdLN and protected from the immunosuppressive TME. Incorporating these highly stemness-equipped Ttsms enhances the response to anti-PD-1 therapy in immune-suppressed brain tumors.
논문정보
- Research article
- 2024년 10월 (BRIC 등록일 2024-10-28)
- 국내 연구진
- 생명과학 > 면역학
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