In:
Gastric Cancer, Springer Science and Business Media LLC, Vol. 26, No. 3 ( 2023-05), p. 393-404
Kurzfassung:
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-1 high compared to CD8PD-1 low 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-1 high tumors have distinct features of an immunologically active, T-cell inflamed TME.
Materialart:
Online-Ressource
ISSN:
1436-3291
,
1436-3305
DOI:
10.1007/s10120-023-01364-7
Sprache:
Englisch
Verlag:
Springer Science and Business Media LLC
Publikationsdatum:
2023
ZDB Id:
1463526-4
ZDB Id:
1481763-9
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