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Cancer Research and Treatment > Accepted Articles
doi: https://doi.org/10.4143/crt.2024.317    [Accepted]
Effector Function Characteristics of Exhausted CD8+ T-cell in Microsatellite Stable and Unstable Gastric Cancer
Dong-Seok Han1 , Yoonjin Kwak2 , Seungho Lee3, Soo Kyung Nam4, Seong-Ho Kong3, Do Joong Park3,5, Hyuk-Joon Lee3,5, Nak-Jung Kwon6, Hye Seung Lee2,5 , Han-Kwang Yang3,5
1Department of Surgery, SMG-SNU Boramae Medical Center, Seoul, Korea
2Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
3Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
4Department of Interdisciplinary Program in Cancer Biology, Seoul National University College of Medicine, Seoul, Korea
5Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
6Macrogen Inc., Seoul, Korea
Correspondence  Hye Seung Lee ,Tel: 82-2-740-8269, Fax: 82-2-744-8273, Email: hye2@snu.ac.kr
Han-Kwang Yang ,Tel: 82-2-2072-3797, Fax: 82-2-3672-0047, Email: hkyang@snu.ac.kr
Received: March 27, 2024;  Accepted: April 11, 2024.  Published online: April 12, 2024.
*Dong-Seok Han and Yoonjin Kwak contributed equally to this work.
ABSTRACT
Purpose
Gastric cancer exhibits molecular heterogeneity, with the microsatellite instability high (MSI-H) subtype drawing attention for its distinct features. Despite a higher survival rate, MSI-H gastric cancer lack significant benefits from conventional chemotherapy. The immune checkpoint inhibitors (ICIs), presents a potential avenue, but a deeper understanding of the tumor immune microenvironment of MSI-H gastric cancer is essential.
Materials and Methods
We explored the molecular characteristics of CD8+ T cell subtypes in three MSI-H and three microsatellite stable (MSS) gastric cancer samples using single-cell RNA sequencing and spatial transcriptome analysis.
Results
In MSI-H gastric cancer, significantly higher proportions of effector memory T cell (Tem), exhausted T cell (Tex), proliferative exhausted T cell (pTex), and proliferative T cell were observed, while MSS gastric cancer exhibited significantly higher proportions of mucosal-associated invariant T (MAIT) cell and NKT cell. In MSI-H gastric cancer, Tex and pTex exhibited a significant upregulation of the exhaustion marker LAG3, as well as elevated expression of effector function markers such as IFNG, GZMB, GZMH, and GZMK, compared to those in MSS gastric cancer. The IFN-γ signaling pathway of Tex and pTex was retained compared to those of MSS gastric cancer. The spatial transcriptome analysis demonstrates the IFN-γ signaling pathway between neighboring Tex and malignant cell, showcasing a significantly elevated interaction in MSI-H gastric cancer.
Conclusion
Our study reveals novel finding indicating that IFN-γ signaling pathway is retained in Tex and pTex of MSI-H gastric cancer, offering a comprehensive perspective for future investigations into immunotherapy for gastric cancer.
Key words: Microsatellite instability, Stomach neoplasms, T-cell exhaustion
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