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. 2023 May;26(3):393-404.
doi: 10.1007/s10120-023-01364-7. Epub 2023 Feb 12.

Clinical relevance of PD-1 positive CD8 T-cells in gastric cancer

Joan Choo #  1 , Ley Fang Kua #  2 , Mu Yar Soe  1 , Bernadette Reyna Asuncion  2 , Benjamin Kye Jyn Tan  3 , Chong Boon Teo  3 , Ryan Yong Kiat Tay  3 , Jimmy So  3   4   5 , Asim Shabbir  3   4 , Kim Guowei  3   4   5 , Hon Lyn Tan  1   5 , Gloria Chan  1 , Haoran Ma  6 , Gokula Krishnan Ramachandran  2 , Jeffrey H Y Lum  7 , Cheng Ean Chee  1 , Sriram Sridharan  2 , Patrick Tan  2   6   5   8   9   10 , Raghav Sundar  1   3   6   5   11 , Wei Peng Yong  12   13   14
Affiliations

Clinical relevance of PD-1 positive CD8 T-cells in gastric cancer

Joan Choo et al. Gastric Cancer. 2023 May.

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.

Keywords: CD8 T-cells; Gastric cancer; Multiplex immunohistochemistry; PD-1.

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Conflict of interest statement

WPY has received Honoraria and consulting fees from Abbvie/Genentech, Amgen, AstraZeneca, Bristol Myers Squibb, Ipsen, Novartis, Bayer, Eisai, Lilly, MSD, Sanofi/Aventis and Taiho Pharmaceutical. RS has received Honoraria from Bristol Myers Squibb, MSD, Lilly, Roche, Taiho Pharmaceutical, AstraZeneca and DKSH; consulting fees from Bristol Myers Squibb, Eisai, Taiho Pharmaceutical, Bayer, Merck, Novartis and MSD; research funding from Paxman and MSD; travel, accommodation funding support from Roche, AstraZeneca, Taiho Pharmaceutical and Eisai. PT has stock and other ownership interests in HealthSeq, research funding from Kyowa Hakko Kirin and Thermo Fisher Scientific, and patents/other intellectual property through the Agency for Science and Technology Research, Singapore (all outside the submitted work). CEC has received Honoraria and consulting fees from AstraZeneca, Roche/Genentech and Guardant Health AMEA; travel and accommodation support from Taiho Pharmaceutical. JC, LFK, MYS, BRA, BKJT, CBT, RYKT, JS, AS, KG, HLT, GC, HM, GKR, JHL, SS declared no conflicts of interest.

Figures

Fig. 1
Fig. 1
Heatmap of baseline clinicopathological characteristics and association with IHC markers of CD8 T-cell PD-1 expression, activation and proliferation
Fig. 2
Fig. 2
High CD8 T-cell PD-1 expression is associated with improved overall survival in gastric cancer
Fig. 3
Fig. 3
High CD8A and High PDCD1 mRNA levels are associated with improved overall survival in gastric cancer. a Overall survival curves of patients enrolled in the Samsung Trial. b Overall survival curves of patients enrolled in the “3G” Trial
Fig. 4
Fig. 4
Single-cell RNA sequencing analyses. UMAP plot representation of 152,423 cells from 40 samples delineating cells expressing CD8 (a), PD1 (b), TIGIT (c) and LAG3 (d). Violin plots indicating the expression levels of TIGIT (e) and LAG3 (f)
See this image and copyright information in PMC

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