Intratumoral PD-1+CD8+ T cells associate poor clinical outcomes and adjuvant chemotherapeutic benefit in gastric cancer

Yu, Kuo-Tsong; Gu, Yun; Zhang, Puran; Fang, Hanji; Cao, Yifan; Wang, Jieti; Lin, Chao; Líu, Hao; Zhang, Heng; He, Hongyong; Li, Ruochen; Qin, Jing; Li, He; Xu, Jiejie

doi:10.1038/s41416-022-01939-8

Cited by 17 publications

(17 citation statements)

References 37 publications

(35 reference statements)

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“…Yu and colleagues recently found that high intratumoral PD-1 positive CD8 T-cells using a cut-off of ≥ 8/HPF was associated with poorer overall survival outcomes as well as poorer efficacy with adjuvant chemotherapy. In this study, the population of CD8 T-cells did not have increased proliferative ability (Ki-67) or cytolytic activity (Granzyme-B), unlike what we observed in our study which may explain some of the differences observed in our study cohort [36]. Saito and colleagues previously reported that higher proportions of PD-1 positive CD8 T-cells present in the circulation portended poorer survival and was also associated with higher stage of disease in gastric cancer [37].…”

Section: Discussioncontrasting

confidence: 94%

“…The role and activation status of infiltrating PD-1 positive CD8 T-cells have been studied in a number of epithelial cancer types such as breast, pancreatic and head and neck tumors showing improved survival outcomes [12][13][14]. However, the prognostic significance of PD-1 positive CD8 T-cells in gastric cancer is poorly understood, and the available data from studies previously conducted is conflicting with several positive [34,35] and negative studies [36,37].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Discussioncontrasting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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“…Recent studies have found that the PD-1 expression is up-regulated in lung cancer, gastric cancer, hepatocellular carcinoma, multiple myeloma, breast cancer, renal cell carcinoma and melanoma [22][23][24][25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

Clinical Implications of Aberrant PD-1 Expression for Acute Leukemia Prognosis

Ruan

Wang

Zhang

et al. 2022

Preprint

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Background: Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are the most common types of leukemia in adults with an overall poor prognosis. PD-1 alone or combined with other immune checkpoint blockade is a promising research direction for the treatment of acute leukemia (AL) patients. However, clinical Implications of aberrant PD-1 expression in peripheral CD4+ and CD8+ T lymphocytes of AML and ALL patients in assessing the prognosis of diseases, remains inconclusive. Methods: In the present study, we used flow cytometry to evaluate PD-1 expression on the surface of CD4+ and CD8+ T lymphocytes in the peripheral circulation of AML and ALL patients and its clinical significance. A total of 53 AML patients, 44 ALL patients and 28 healthy controls were enrolled in this study and peripheral blood specimens were detected by flow cytometry. Results: Our results indicated that percentages of CD4+PD1+ and CD8+PD1+ T lymphocytes in newly diagnosed and non-remission groups were significantly higher than healthy control both in AML and ALL patients. The high level of CD4+PD1+ and CD8+PD1+ T lymphocyteswere respectively poor prognostic indicators of AML patients and ALL patients but had no significant correlation with most common clinical risks. Conclusions: Our findings show that aberrant PD-1 expression correlates with the prognosis of AL patient and may thus serve as poor prognostic indicators. Immunotherapy using PD-1 inhibitors may be a promising strategy for AML and ALL patients with peripheral circulating CD4+PD1+ and CD8+PD1+ T lymphocytes positively expressed, respectively.

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“…Considering interaction between PD-L1 including exoPD-L1 and PD-1 receptor on PD-1 + CD8 + T cells might result in dysfunction and exhaustion of the T cells and enhanced TGF-β signaling in tumor microenvironment, higher level of PD-1 + CD8 + T cells in high exoPD-L1 group might also indicate immunosuppressive status of the disease 39 . Kuan et al recently published a study that showed PD-1 + CD8 + T cells abundance in the tumor microenvironment is associated with T-cell exhaustion and enhanced TGF-β signaling, and predicts poor prognosis in stage I-III gastric cancer 40 . Saito et al also showed that circulating PD-1 + CD8 + T cells may predict the prognosis of patients with stage I-III gastric cancer 41 .…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of soluble PD-L1 and exosomal PD-L1 in advanced gastric cancer patients receiving systemic chemotherapy

Shin

Kim

Park

et al. 2023

Sci Rep

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The prognostic role of soluble PD-L1 (sPD-L1) and exosomal PD-L1 (exoPD-L1) in patients with gastric cancer (GC) receiving systemic chemotherapy remains unelucidated. Thus, we examined their prognostic significance in patients with advanced GC. Blood samples were obtained from 99 patients with advanced GC receiving first-line chemotherapy. Serum-derived exosomes were isolated by centrifugation and polymer precipitation. The correlation between serum-derived exoPD-L1, plasma sPD-L1, immune-related markers, and circulating immune cells was evaluated. Patients were divided into two groups according to pretreatment sPD-L1 and exoPD-L1 levels: low sPD-L1 and high sPD-L1 groups, low exoPD-L1 and high exoPD-L1 groups. Patients with low sPD-L1 level before treatment (< 9.32 pg/mL) showed significantly better overall survival (OS) and progression-free survival (PFS) than those with high sPD-L1 level (≥ 9.32 pg/mL). The low exoPD-L1 group (< 10.21 pg/mL) showed a tendency of longer PFS than the high exoPD-L1 group (≥ 10.21 pg/mL). Pretreatment sPD-L1 was an independent prognostic factor for OS in multivariate analysis. exoPD-L1 was associated with systemic inflammation markers, immunomodulatory cytokines, and T cells, while sPD-L1 was associated with tumor markers. Pretreatment plasma-derived sPD-L1 level could be used as a prognostic marker for patients receiving cytotoxic chemotherapy. Serum-derived exoPD-L1 may reflect the immunosuppressive state of patients with advanced GC.

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Intratumoral PD-1+CD8+ T cells associate poor clinical outcomes and adjuvant chemotherapeutic benefit in gastric cancer

Cited by 17 publications

References 37 publications

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

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

Clinical Implications of Aberrant PD-1 Expression for Acute Leukemia Prognosis

Prognostic value of soluble PD-L1 and exosomal PD-L1 in advanced gastric cancer patients receiving systemic chemotherapy

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