S2042 CD8+ T Cell Infiltration and Decreased FOXP3+ Regulatory T Cell Numbers in the Primary Tumor Predict for Survival in Gastric Cancer Patients

e16578 Background: Previous data has shown that a positive response to immunotherapy usually relies on active interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). The aim of this study was to classify gastric cancer (GC) subsets based on the TME immune status according to the expression of PD-L1 and infiltration of CD8+ T cells. Methods: One hundred and eighty-six tumor tissue from gastric cancer patients with a curative D2 gastrectomy were examined for evaluating PD-L1 and CD8+ T cells status using histopathologic analysis. The molecular characteristics of 289 GC samples in TCGA network were further analyzed to distinguish the genetic features of four immune subtypes depending on the presence of PD-L1/CD8+T cell. Results: GC samples were categorized into four types, type I (CD8+/PD-L1+, 60.3%), II (CD8-/PD-L1-, 11.8%), III (CD8-/PD-L1+, 0%), and IV (CD8+/PD-L1-, 27.9%), basing on PD-L1/CD8 expression. The PD-L1 expressing level was geographically associated with the intensity of CD8+ T cell infiltration which was significantly associated with disease-free survival (DFS) and overall survival (OS) (p = 0.003 and p = 0.006). Distinct patterns of genetic profile were described in four types of GC from TCGA database. Type I and III which PD-L1 were overly expressed had comparatively higher MSI and TMB, with EBV mainly enriched in Type I, whereas CIN was more likely to occur in PD-L1 aberrant types II and IV. SNV analysis illustrated higher gene mutations in oncogenes (PIK3CA and ERBB2), and in DNA damage repair related pathway, such as PRKDC, ATM, and SWI/SNF complexes (e.g. ARID1A) in Type I. However, TP53 mutations tend to enrich in Type II and IV. Similar results were obtained by transcriptome analysis. Conclusions: The genetic features of four immune subtypes proof that PD-L1 and CD8+ T cells status are reasonable immunogenomic classification of gastric cancer. SNV analysis prompts a potential mechanism for effectiveness of immunotherapy in Type I patients. Overall, the results may be useful for the development of clinical treatments for the blockade of immune checkpoints.

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Therapeutic efficacy of antitumor dendritic cell vaccinations correlates with persistent Th1 responses, high intratumor CD8+ T cell recruitment and low relative regulatory T cell infiltration

Cancer Immunology Immunotherapy ◽

10.1007/s00262-008-0500-y ◽

2008 ◽

Vol 57 (12) ◽

pp. 1745-1756 ◽

Cited By ~ 16

Author(s):

Gregory Driessens ◽

Laurence Gordower ◽

Lise Nuttin ◽

Patrick Stordeur ◽

Didier Blocklet ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

Regulatory T Cell ◽

Therapeutic Efficacy ◽

Cd8 T Cell ◽

Cell Infiltration ◽

Cell Recruitment ◽

T Cell Infiltration

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Association of tumor infiltrating CD8 positive T cells and PDL-1 expression with survival after conversion surgery for unresectable gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.62 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 62-62

Author(s):

Hiroaki Tanaka ◽

Junya Nishimura ◽

Yuichiro Miki ◽

Tatsuro Tamura ◽

Kazuya Muguruma ◽

...

Keyword(s):

Gastric Cancer ◽

Survival Rate ◽

T Cell ◽

Cd8 T Cell ◽

High Expression ◽

Cell Infiltration ◽

Conversion Surgery ◽

T Cell Infiltration ◽

High Expression Group ◽

Unresectable Gastric Cancer

62 Background: Conversion surgery after chemotherapy responds to unresectable gastric cancer has long-term prognosis, however, chemotherapy after surgery should also be considered to improve treatment outcome. The effectiveness of immune checkpoint inhibitors for gastric cancer has been proved. In this study, we investigated the association between PDL-1 expression and CD8+ T cell infiltration in the primary tumor and prognosis of patients who underwent conversion surgery after S-1-based multidrug chemotherapy in unresectable gastric cancer. Methods: We evaluated PDL-1 expression and CD8 T cell infiltration by immunohistochemical staining and examined the relationship with prognosis in 90 patients with Stage IV gastric cancer who underwent gastrectomy in our department from 2007 to 2015. Results: 90 cases included 47 cases of palliative resection, 26 cases of CY1P 0cases and 17 cases of conversion surgery. Among Conversion Surgery cases, 11 (65%) patients underwent R0 surgery, and the 5-year survival rate was 66%. The 5-year survival rate of non-curative resected cases was 16%. In immunohistochemical examination, PDL-1 high expression was a poor prognostic factor in palliative surgery and CY1P0 cases. Meanwhile, in the case of Conversion Surgery, the 5-year survival rate was 58%, 32%, 61%, and 30% in the order of PDL-1 high expression group, low expression group, CD8 T cell high infiltration, and low infiltration group, respectively. Prognosis of PDL-1 high expression group and CD8 T cell infiltration group was good. There was no association between curative resection and neither of CD8 T cell infiltration or PDL-1 expression. Conclusions: We found that the prognosis was relatively good in patients where local immune response was enhanced, regardless of R0 excision. Our results suggested that infiltration of CD8 T cells in the primary tumor may be a prognostic predictor, and it is expected to use an immune check point inhibitor after conversion surgery for unresectable gastric cancer.

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Interleukin-10 expression significantly correlates with minor CD8+T-cell infiltration and high microvessel density in patients with gastric cancer

International Journal of Cancer ◽

10.1002/ijc.21598 ◽

2005 ◽

Vol 118 (8) ◽

pp. 1909-1914 ◽

Cited By ~ 35

Author(s):

Teruhisa Sakamoto ◽

Hiroaki Saito ◽

Shigeru Tatebe ◽

Shunichi Tsujitani ◽

Mitsuhiko Ozaki ◽

...

Keyword(s):

Gastric Cancer ◽

T Cell ◽

Microvessel Density ◽

Cd8 T Cell ◽

Interleukin 10 ◽

Cell Infiltration ◽

T Cell Infiltration

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Disruption of Wnt/β-catenin Pathway Elevates the Sensitivity of Gastric Cancer Cells to PD-1 Antibody

Current Molecular Pharmacology ◽

10.2174/1874467214666210617163821 ◽

2021 ◽

Vol 14 ◽

Author(s):

Jian Li ◽

Hui Zhang ◽

Songhua Bei ◽

Xiaohong Zhang ◽

Huanqing Li ◽

...

Keyword(s):

Gastric Cancer ◽

T Cell ◽

Cell Apoptosis ◽

Therapeutic Efficacy ◽

Cd8 T Cell ◽

Jurkat Cells ◽

Cell Infiltration ◽

Clinical Samples ◽

Apoptosis Rate ◽

T Cell Infiltration

Background: Gastric cancer (GC) is the fifth most common malignancy tumor and the third cause of cancer-related death around the world. Immune checkpoint inhibitors (ICIs) such as programmed cell death-1 (PD-1) antibodies play an active role in tumor therapy. A recent study reveals that the Wnt/β-catenin signaling pathway is negatively correlated with T-cell infiltration in the tumor microenvironment (TME), thereby influencing the therapeutic efficacy of the PD-1 antibody. Objective: In this study, we aimed to uncover the relationship of the Wnt/β-catenin pathway to CD8+ T cell activity as well as its effect on anti-PD-1 therapeutic efficacy in GC. Methods: We first collected clinical samples and went through an immunohistochemical analysis and found that a high β-catenin expression in GC tissues was often associated with a significant absence of CD8+ T-cell infiltration. Results: In addition, our data further indicated that disruption of the Wnt/β-catenin pathway in GC cells inhibited their migratory and invasive ability. Meanwhile, enhanced sensitivity of GC cells to PD-1 blockade therapy was evident by decreased Jurkat cell apoptosis rate and increased GC cell apoptosis rate in a tumor and Jurkat cells co-culture system with the presence of Wnt/β-catenin pathway inhibition. Conclusion: Collectively, these findings indicated that the Wnt/β-catenin pathway might play a significant role in modulating the activity of Jurkat cells, and downregulation of Wnt/β-catenin may enhance the sensitivity of GC cells to PD-1 antibody in vitro. This result further indicated that β-catenin and PD-1 targeted inhibition might become a potential and effective therapy for GC patients.

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