Dataset Information

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

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-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.

SUBMITTER: Choo J

PROVIDER: S-EPMC10115710 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

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

Choo Joan J Kua Ley Fang LF Soe Mu Yar MY Asuncion Bernadette Reyna BR Tan Benjamin Kye Jyn BKJ Teo Chong Boon CB Tay Ryan Yong Kiat RYK So Jimmy J Shabbir Asim A Guowei Kim K Tan Hon Lyn HL Chan Gloria G Ma Haoran H Ramachandran Gokula Krishnan GK Lum Jeffrey H Y JHY Chee Cheng Ean CE Sridharan Sriram S Tan Patrick P Sundar Raghav R Yong Wei Peng WP

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 20230212 3

<h4>Background</h4>We evaluated the relevance of PD-1<sup>+</sup>CD8<sup>+</sup> T-cells in gastric cancer (GC) including prognostic significance, association with chemotherapy and immunotherapy sensitivity and correlations with the tumor microenvironment (TME).<h4>Methods</h4>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 ...[more]

PMID: 36781556

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Project description:BackgroundPrevious studies have shown that PD-L1-positive advanced gastric cancer (GC) patients could achieve clinical benefit after receiving immune checkpoint inhibitors (ICI) in initial or subsequent therapy. A number of prospective studies such as Keynote-158 have demonstrated that PD-L1-negative patients who tested as microsatellite instability-high (MSI-H) or tumor mutational burden-high (TMB-H) can benefit from ICIs. In the search for more biomarker for immunotherapy, some studies showed that patients with a specific characteristic to tumor microenvironment (TME) were associated with better prognosis. This study aimed to explore the association between the TME and immunotherapy in PD-L1 negative GC patients.MethodsThis study was a retrospective cohort study. Twenty-six CPS PD-L1 negative stage IV advanced GC patients treated with chemoimmunotherapy in Shenzhen Hospital of Peking University were retrospectively enrolled according to the inclusion criteria. Their clinical characteristics were assessed and recorded by independent clinicians. Follow-up data was conducted through the Internet or visit. Respond to treatment was evaluated by RECIST 1.1. The primary outcome was progression-free survival (PFS). The level of tumor-infiltrating lymphocytes (TILs) was measured by multiplex immunofluorescence (mIF) among these patients. Cox proportional hazards analysis was performed to analyzed the correlation between PFS and clinical characteristics including TILs.ResultsAmong 26 patients, 5 patients (19.2%) were on complete response (CR) and 9 patients (34.6%) were in partial response (PR), while 7 patients (26.9%) experienced stable disease (SD). Intratumoral CD8+ T cells were obviously increased in CPS PD-L1 negative patients who responded to chemoimmunotherapy, compared with patients who did not respond (P=0.011). And higher level of CD8+ TILs was demonstrated to associate with better PFS in CPS PD-L1-negative patients treated with chemoimmunotherapy (HR =23.70, 95% CI: 1.15-488.30, P=0.04).ConclusionsIntratumoral CD8+ TILs may be a potential positive predictive factor of clinical response for chemoimmunotherapy in PD-L1-negative advanced GC. However, the results need to be further confirmed in a cohort with more subjects due to a limited sample sizes in present study.

Project description:Recent progress in single-cell profiling technologies has revealed significant phenotypic and transcriptional heterogeneity in tumor-infiltrating CD8+ T cells. However, the transition between the different states of intratumoral antigen-specific CD8+ T cells remains elusive. Here, we sought to examine the generation, transcriptomic states, and the clinical relevance of melanoma-infiltrating CD8+ T cells expressing a chemokine receptor and T-cell differentiation marker, CX3C chemokine receptor 1 (CX3CR1). Analysis of single-cell datasets revealed distinct human melanoma-infiltrating CD8+ T-cell clusters expressing genes associated with effector T-cell function but with distinguishing expression of CX3CR1 or PDCD1. No obvious impact of CX3CR1 expression in melanoma on the response to immune checkpoint inhibitor therapy was observed while increased pretreatment and on-treatment frequency of a CD8+ T-cell cluster expressing high levels of exhaustion markers was associated with poor response to the treatment. Adoptively transferred antigen-specific CX3CR1- CD8+ T cells differentiated into the CX3CR1+ subset in mice treated with FTY720, which inhibits lymphocyte egress from secondary lymphoid tissues, suggesting the intratumoral generation of CX3CR1+ CD8+ T cells rather than their trafficking from secondary lymphoid organs. Furthermore, analysis of adoptively transferred antigen-specific CD8+ T cells, in which the Cx3cr1 gene was replaced with a marker gene confirmed that CX3CR1+ CD8+ T cells could directly differentiate from the intratumoral CX3CR1- subset. These findings highlight that tumor antigen-specific CX3CR1- CD8+ T cells can fully differentiate outside the secondary lymphoid organs and generate CX3CR1+ CD8+ T cells in the tumor microenvironment, which are distinct from CD8+ T cells that express markers of exhaustion.SignificanceIntratumoral T cells are composed of heterogeneous subpopulations with various phenotypic and transcriptional states. This study illustrates the intratumoral generation of antigen-specific CX3CR1+ CD8+ T cells that exhibit distinct transcriptomic signatures and clinical relevance from CD8+ T cells expressing markers of exhaustion.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

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