1. Clinical relevance of PD-1 positive CD8 T-cells in gastric cancer.
- Author
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Choo J, Kua LF, Soe MY, Asuncion BR, Tan BKJ, Teo CB, Tay RYK, So J, Shabbir A, Guowei K, Tan HL, Chan G, Ma H, Ramachandran GK, Lum JHY, Chee CE, Sridharan S, Tan P, Sundar R, and Yong WP
- Subjects
- Humans, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor metabolism, Granzymes metabolism, Clinical Relevance, Ki-67 Antigen metabolism, Lymphocytes, Tumor-Infiltrating pathology, Prognosis, Tumor Microenvironment, B7-H1 Antigen metabolism, CD8-Positive T-Lymphocytes, Stomach Neoplasms genetics, Stomach Neoplasms therapy, Stomach Neoplasms metabolism
- Abstract
Background: We evaluated the relevance of PD-1
+ CD8+ T-cells in gastric cancer (GC) including prognostic significance, association with chemotherapy and immunotherapy sensitivity and correlations with the tumor microenvironment (TME)., Methods: Discovery cohort: GC samples were evaluated for AE1/3, CD8, PD-1, Ki-67 and Granzyme-B expression with fluorescence-based multiplex immunohistochemistry (mIHC). Validation cohorts: we analyzed bulk RNAseq GC datasets from TCGA, the "3G" chemotherapy trial and an immunotherapy phase 2 trial. The cox proportional hazards model was used to identify factors that influenced overall survival (OS). To study the TME, we analyzed single-cell RNAseq performed on GCs., Results: In the discovery cohort of 350 GCs, increased PD-1 expression of CD8 T-cells was prognostic for OS (HR 0.822, p = 0.042). PD-1 expression in CD8 T-cells highly correlated with cytolytic [Granzyme-B+ ] (r = 0.714, p < 0.001) and proliferative [Ki-67+ ] (r = 0.798, p < 0.001) activity. Analysis of bulk RNAseq datasets showed tumors with high PD-1 and CD8A expression levels had improved OS when treated with immunotherapy (HR 0.117, p = 0.036) and chemotherapy (HR 0.475, p = 0.017). Analysis of an scRNAseq dataset of 152,423 cells from 40 GCs revealed that T-cell and NK-cell proportions were higher (24% vs 18% and 19% vs 15%, p < 0.0001), while macrophage proportions were lower (7% vs 11%, p < 0.0001) in CD8PD-1high compared to CD8PD-1low tumors., Conclusion: This is one of the largest GC cohorts of mIHC combined with analysis of multiple datasets providing orthogonal validation of the clinical relevance of PD-1+ CD8+ T-cells being associated with improved OS. CD8PD-1high tumors have distinct features of an immunologically active, T-cell inflamed TME., (© 2023. The Author(s).)- Published
- 2023
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