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2 "T-cell exhaustion"
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Gastrointestinal cancer
Effector Function Characteristics of Exhausted CD8+ T-Cell in Microsatellite Stable and Unstable Gastric Cancer
Dong-Seok Han, Yoonjin Kwak, Seungho Lee, Soo Kyung Nam, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Nak-Jung Kwon, Hye Seung Lee, Han-Kwang Yang
Cancer Res Treat. 2024;56(4):1146-1163.   Published online April 12, 2024
DOI: https://doi.org/10.4143/crt.2024.317
AbstractAbstract PDFPubReaderePub
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, 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 cell and natural killer T 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 interferon γ (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.

Citations

Citations to this article as recorded by  
  • Simvastatin induces ferroptosis and activates anti-tumor immunity to sensitize anti-PD-1 immunotherapy in microsatellite stable gastric cancer
    Yumei Ning, Shilin Fang, Runan Zhang, Jun Fang, Kun Lin, Yang Ding, Haihang Nie, Jingkai Zhou, Qiu Zhao, Hengning Ke, Haizhou Wang, Fan Wang
    International Immunopharmacology.2024; 142: 113244.     CrossRef
  • 2,355 View
  • 164 Download
  • 1 Crossref
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Genitourinary cancer
Favorable Immunotherapy Plus Tyrosine Kinase Inhibition Outcome of Renal Cell Carcinoma Patients with Low CDK5 Expression
Xianglai Xu, Ying Wang, Zhaoyi Chen, Yanjun Zhu, Jiajun Wang, Jianming Guo
Cancer Res Treat. 2023;55(4):1321-1336.   Published online April 3, 2023
DOI: https://doi.org/10.4143/crt.2022.1532
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Immunotherapy (IO) plus tyrosine kinase inhibitor (TKI) has become the first-line treatment for advanced renal cell carcinoma, despite the lack of prognostic biomarkers. Cyclin-dependent kinase 5 (CDK5) affects the tumor microenvironment, which may influence the efficacy of TKI+IO.
Materials and Methods
Two cohorts from our center (Zhongshan Metastatic Renal Cell Carcinoma [ZS-MRCC] cohort, Zhongshan High-risk Localized Renal Cell Carcinoma [ZS-HRRCC] cohort) and one cohort from a clinical trial (JAVELIN-101) were enrolled. The expression of CDK5 of each sample was determined by RNA sequencing. Immune infiltration and T cell function were evaluated by flow cytometry and immunohistochemistry. Response and progression-free survival (PFS) were set as primary endpoints.
Results
Patients of low CDK5 expression showed higher objective response rate (60.0% vs. 23.3%) and longer PFS in both cohorts (ZS-MRCC cohort, p=0.014; JAVELIN-101 cohort, p=0.040). CDK5 expression was enhanced in non-responders (p < 0.05). In the ZS-HRRCC cohort, CDK5 was associated with decreased tumor-infiltrating CD8+ T cells, which was proved by immunohistochemistry (p < 0.05) and flow cytometry (Spearman’s ρ=–0.49, p < 0.001). In the high CDK5 subgroup, CD8+ T cells revealed a dysfunction phenotype with decreased granzyme B, and more regulatory T cells were identified. A predictive score was further constructed by random forest, involving CDK5 and T cell exhaustion features. The RFscore was also validated in both cohorts. By utilizing the model, more patients might be distinguished from the overall cohort. Additionally, only in the low RFscore did TKI+IO outperform TKI monotherapy.
Conclusion
High-CDK5 expression was associated with immunosuppression and TKI+IO resistance. RFscore based on CDK5 may be utilized as a biomarker to determine the optimal treatment strategy.

Citations

Citations to this article as recorded by  
  • SPP1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinoma
    Xianglai Xu, Jinglai Lin, Jiahao Wang, Ying Wang, Yanjun Zhu, Jiajun Wang, Jianming Guo
    Human Vaccines & Immunotherapeutics.2024;[Epub]     CrossRef
  • Efficacy and Safety of Immuno-Oncology Plus Tyrosine Kinase Inhibitors as Late-Line Combination Therapy for Patients with Advanced Renal Cell Carcinoma
    Shuzo Hamamoto, Yoshihiko Tasaki, Toshiharu Morikawa, Taku Naiki, Toshiki Etani, Kazumi Taguchi, Shoichiro Iwatsuki, Rei Unno, Tomoki Takeda, Takashi Nagai, Kengo Kawase, Yoshihisa Mimura, Yosuke Sugiyama, Atsushi Okada, Yoko Furukawa-Hibi, Takahiro Yasui
    Journal of Clinical Medicine.2024; 13(12): 3365.     CrossRef
  • PSMD2 overexpression as a biomarker for resistance and prognosis in renal cell carcinoma treated with immune checkpoint and tyrosine kinase inhibitors
    Xianglai Xu, Jiahao Wang, Ying Wang, Yanjun Zhu, Jiajun Wang, Jianming Guo
    Cellular Oncology.2024; 47(5): 1943.     CrossRef
  • External validation of hemoglobin and neutrophil levels as predictors of the effectiveness of ipilimumab plus nivolumab for treating renal cell carcinoma
    Shuzo Hamamoto, Yoshihiko Tasaki, Shimpei Yamashita, Junya Furukawa, Kazutoshi Fujita, Ryotaro Tomida, Makito Miyake, Noriyuki Ito, Hideto Iwamoto, Yosuke Sugiyama, Kazumi Taguchi, Takahiro Yasui
    Frontiers in Oncology.2024;[Epub]     CrossRef
  • 3,207 View
  • 186 Download
  • 5 Web of Science
  • 4 Crossref
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