The increase of CD57+ T cells in the peripheral blood and their impaired immune functions in patients with advanced gastric cancer

We aimed to investigate the prognostic value of the immune cells population in peripheral blood from patients with advanced gastric cancer treated with neoadjuvant chemotherapy. A total of 105 patients with advanced gastric cancer were evaluated in this study. Blood samples were collected before and 1 week after the last dose of chemotherapy. The percentage of CD3+, CD3+CD4+, CD3+CD8+, and CD4+CD25+Foxp3+ T cells was assessed using flow cytometry analysis. The relationship between T cell subsets and clinical outcome was evaluated. The percentage of CD3+CD8+ lymphocytes was significantly increased after chemotherapy and CD4+CD25+Foxp3+ regulatory T cells (Tregs) decreased ( p = 0.003 and p < 0.001, respectively). The percentage of CD3+CD8+ lymphocytes and Tregs was strongly associated with response to chemotherapy ( p = 0.017 and p < 0.030, respectively). Patients with high CD3+CD8+ T cells and low CD4+CD25+Foxp3+ Tregs had significantly increased overall survival ( p = 0.012 and p = 0.048, respectively). Neither CD3+ nor CD3+CD4+ T cells showed significant changes after chemotherapy or correlations with the clinical outcome. The positive correlation between a high CD3+CD8+ T cells or low CD4+CD25+Foxp3+ Tregs and clinical outcome indicates its key role in the prognosis of gastric cancer patients and may serve as a biomarker to identify patients likely to benefit from neoadjuvant chemotherapy.

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Peripheral blood T lymphocytes are downregulated by the PD-1/PD-L1 axis in advanced gastric cancer

Archives of Medical Science ◽

10.5114/aoms.2018.75092 ◽

2019 ◽

Vol 15 (3) ◽

pp. 774-783 ◽

Cited By ~ 4

Author(s):

Witold Zgodzinski ◽

Ewelina Grywalska ◽

Krzysztof Zinkiewicz ◽

Agata Surdacka ◽

Marek Majewski ◽

...

Keyword(s):

Gastric Cancer ◽

T Lymphocytes ◽

Advanced Gastric Cancer ◽

Peripheral Blood

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Transfer of the ADA gene into human ADA-deficient T lymphocytes reconstitutes specific immune functions

Blood ◽

10.1182/blood.v80.5.1120.1120 ◽

1992 ◽

Vol 80 (5) ◽

pp. 1120-1124 ◽

Cited By ~ 28

Author(s):

G Ferrari ◽

S Rossini ◽

N Nobili ◽

D Maggioni ◽

A Garofalo ◽

...

Keyword(s):

T Cells ◽

Enzyme Activity ◽

Gene Transfer ◽

Peripheral Blood ◽

Retroviral Vector ◽

Peripheral Blood Lymphocytes ◽

Proliferative Potential ◽

Immune Functions ◽

Beta Gene

Abstract Peripheral blood lymphocytes obtained from a patient affected by adenosine deaminase (ADA) deficiency and severe combined immunodeficiency were infected with a retroviral vector containing two copies of a human ADA minigene, and injected into bg/nu/xid (BNX) immunodeficient mice. Six to 10 weeks after injection, human T cells were cloned from the spleens of recipient animals and analyzed for proliferative potential, T-cell surface markers, expression of ADA activity, integration of retroviral sequences, T-cell receptor (TCR) beta gene rearrangement, and specificity of antigen recognition. Efficient gene transfer and expression restored proliferative potential in vitro and long-term survival in vivo. All clonable human T lymphocytes obtained from the spleen of recipient animals had high levels of vector-derived ADA enzyme activity and showed predominantly the CD4+ phenotype. Retroviral integrations and TCR-beta gene rearrangements demonstrated the presence of a variety of different clones in the spleens of recipient mice. Furthermore, the combined analyses of vector integration and TCR rearrangement provided evidence that a circulating progenitor cell was transduced by the retroviral vector, giving rise to different and functional TCRs. Evaluation of antigen-specificity demonstrated both alloreactive and foreign antigen specific immune responses. These results suggest that restoration of enzyme activity in human ADA-deficient peripheral blood T cells by retroviral-mediated ADA gene transfer allows in vivo survival and reconstitution of specific immune functions. Therefore, retroviral vector-mediated gene transfer into circulating mononuclear cells could be successful not only in maintaining the metabolic homeostasis, but also for the development of a functional immune repertoire. This is a fundamental prerequisite for the usage of genetically engineered peripheral blood lymphocytes for somatic cell gene therapy of ADA deficiency.

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Immunological impact of ramucirumab on tumor microenvironment in advanced gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.98 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 98-98 ◽

Cited By ~ 1

Author(s):

Yosuke Togashi ◽

Yasuko Tada ◽

Daisuke Kotani ◽

Akihito Kawazoe ◽

Toshihiko Doi ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Advanced Gastric Cancer ◽

Mononuclear Cells ◽

Low Frequency ◽

Progression Free Survival ◽

Tumor Infiltrating Lymphocytes ◽

Peripheral Blood Mononuclear ◽

Primary Tumors ◽

Significant Difference

98 Background: Ramucirumab (RAM), a monoclonal antibody against VEGFR2, was recently approved for the treatment of advanced gastric cancer (GC). However, little is known about the immunological effects in advanced GC patients. Methods: Patients with advanced GC who had been planned to receive chemotherapy containing RAM were prospectively enrolled for this study from January 2016 to September 2016. Paired samples were obtained from peripheral blood mononuclear cells (PBMCs) and tumor infiltrating lymphocytes (TILs) in primary tumors pre- and post-RAM therapy to investigate immune profiles. Results: A total of 59 PBMCs and TILs from 18 patients were collected. Higher frequencies of FOXP3highCD45RA-CD4+ T cells (effector regulatory T cells: eTregs) were detected in TILs compared with PBMCs (19.05±10.48% vs 1.89±1.0%, P < 0.0001), and the presence of high eTreg in TILs was not reflected in PBMCs. eTregs of TILs, but not of PBMC were significantly decreased after RAM-containing therapies (22.67±11.19% vs. 16.33±8.44%, P = 0.034). Expressions of immune checkpoint (IC) molecules (PD-1, CTLA-4, LAG-3, and ICOS) were much higher in TILs than those in PBMCs, and all these molecules exhibited higher expressions on eTregs than on CD8+ T cells. Among them, ICOS was specifically expressed by eTregs in TILs. PD-1+CD8+ T cells in TILs were significantly decreased after RAM-containing therapies (54.99±19.06% vs. 39.23±17.15%, P = 0.0005), but not in PBMC. Patients with partial responses had significantly higher frequency of eTreg in pre-treatment TIL than those with progression disease (32.56±12.11% vs. 14.83±3.18%, P = 0.036). Furthermore, patients with high eTreg frequency had significantly longer progression-free survival than those with low frequency (161 days vs. 76 days, P = 0.024). Conclusions: There was significant difference in immune profile between PBMC and TIL in GC patients. eTregs and PD-1 expression on CD8+T cells in TILs, not in PBMCs were decreased after RAM-containing therapies. This observation suggests the importance of TIL analyses and might be a rationale to use RAM as an immunomodulator in combination with IC inhibitors.

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The effect of peripheral blood values on prognosis of patients with locally advanced gastric cancer before treatment

Medical Oncology ◽

10.1007/s12032-009-9335-4 ◽

2009 ◽

Vol 27 (4) ◽

pp. 1060-1065 ◽

Cited By ~ 77

Author(s):

Mehmet Aliustaoglu ◽

Ahmet Bilici ◽

Bala Basak Oven Ustaalioglu ◽

Volkan Konya ◽

Murat Gucun ◽

...

Keyword(s):

Gastric Cancer ◽

Advanced Gastric Cancer ◽

Peripheral Blood ◽

Locally Advanced ◽

Locally Advanced Gastric Cancer

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Application of Circulating Tumor Cells and Circulating Free DNA from Peripheral Blood in the Prognosis of Advanced Gastric Cancer

Journal of Oncology ◽

10.1155/2022/9635218 ◽

2022 ◽

Vol 2022 ◽

pp. 1-9

Author(s):

Pengjie Yu ◽

Shengmao Zhu ◽

Yushuang Luo ◽

Ganggang Li ◽

Yongqiang Pu ◽

...

Keyword(s):

Gastric Cancer ◽

Neoadjuvant Chemotherapy ◽

Neoadjuvant Therapy ◽

Advanced Gastric Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Peripheral Blood ◽

Circulating Free Dna ◽

Free Dna ◽

N Stage

Objective. To explore the application value of circulating tumor cells (CTCs) and circulating free DNA (cfDNA) from peripheral blood in the prognosis of advanced gastric cancer (AGC). Here, we measured CTCs and cfDNA quantity for predicting the outcome of patients. Patients and Methods. Forty-five patients with advanced gastric cancer who underwent neoadjuvant chemotherapy and surgical treatment were enrolled in this study. All patients received neoadjuvant chemotherapy with paclitaxel + S-1 + oxaliplatin (PSOX) regimen, and CTCs and cfDNA of the peripheral blood were detected before and after neoadjuvant therapy. Relationships between the number/type of CTC or cfDNA and the efficacy of neoadjuvant chemotherapy were analyzed. Results. Among 45 patients, 43 (95.6%) were positive, and the positive rate of mesenchymal CTC was increased with the increase in the T stage. The proportion of mesenchymal CTC was positively correlated with the N stage ( P < 0.05 ), and the larger N stage will have the higher proportion of mesenchymal CTC. Patients with a small number of mesenchymal CTC before neoadjuvant chemotherapy were more likely to achieve partial response (PR) with neoadjuvant therapy. Patients with positive CA-199 were more likely to achieve PR with neoadjuvant therapy ( P < 0.05 ). Patients in the PR group were more likely to have decreased/unchanged cfDNA concentration after neoadjuvant therapy ( P = 0.119 ). After neoadjuvant therapy (before surgery), the cfDNA concentration was higher and the efficacy of neoadjuvant therapy (SD or PD) was lower ( P = 0.045 ). Conclusions. Peripheral blood CTC, especially interstitial CTC and cfDNA, has a certain value in predicting the efficacy and prognosis of neoadjuvant chemotherapy in advanced gastric cancer.

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CD137 Agonist Induces Gastric Cancer Cell Apoptosis by Enhancing The Functions of CD8+ T Cells via NF-κB Signaling

10.21203/rs.3.rs-40870/v1 ◽

2020 ◽

Author(s):

Ben-Shun Hu ◽

Tian Tang ◽

Tie-Long Wu ◽

Ying-Yue Sheng ◽

Yu-Zheng Xue

Keyword(s):

Gastric Cancer ◽

Flow Cytometry ◽

T Cells ◽

Real Time ◽

Peripheral Blood ◽

Cell Apoptosis ◽

Nuclear Translocation ◽

Granzyme B ◽

Ifn Γ

Abstract Background: CD137 is identified as a target for tumor immunotherapy. However, the role of CD137 in gastric cancer (GC), especially in inducing GC cell apoptosis has not been studied yet. Methods: Foxp3+ and CD8+ T cells in GCs were investigated by immunohistochemistry (IHC). CD137 expression in GCs was detected by flow cytometry, IHC and immunofluorescence (IF). Peripheral blood mononuclear cells (PBMCs) and CD8+ T cells isolated from peripheral blood were stimulated with a CD137 agonist in vitro. CD8+ T cells proliferation and p65 expression were explored by flow cytometry. p65 nuclear translocation was analyzed by IF. IL-10, TGF-β, IFN-γ, Perforin and Granzyme B were detected by real-time quantitative PCR (real-time PCR). PBMCs and primary GC cells were cocultured and stimulated with the CD137 agonist in vitro. Apoptosis of the primary GC cells was detected by flow cytometry. Results: Our data demonstrated that GC tumors show characteristics of an immunosuppressive microenvironment. CD137 was predominantly expressed in CD8+ T cells in GCs and had a positive correlation with tumor cell differentiation. CD137 agonist promoted CD8+ T cells proliferation and increased the secretion of IFN-γ, Perforin and Granzyme B, which induced primary GC cell apoptosis. Mechanistically, this study found that CD137 agonist could induce NF-κB nuclear translocation in CD8+ T cells. Conclusion: Our results demonstrate that CD137 agonist can induce primary GC cell apoptosis by enhancing CD8+ T cells via activating NF-κB signaling.

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Combined chemotherapy of platinum and fluorouracil promotes T cell–mediated antitumor immunity

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa143 ◽

2020 ◽

Author(s):

Yixiao Luo ◽

Siyu Pei ◽

Jing Xu ◽

Yichuan Xiao ◽

Xiaodong Zhu

Keyword(s):

Gastric Cancer ◽

T Cells ◽

T Cell ◽

Advanced Gastric Cancer ◽

T Cell Activation ◽

Antitumor Immunity ◽

Cell Activation ◽

Mouse Tumor ◽

Combined Chemotherapy ◽

Long Term Treatment

Abstract The two-drug combined chemotherapy of platinum and fluorouracil has been reported to efficiently kill tumor cells as the first-line treatment for advanced gastric cancer. However, the effect of these drugs on T cells remains unclear. Here, we showed that T cells including CD4+ T cells and CD8+ T cells of the patients with advanced gastric cancer after platinum and fluorouracil chemotherapy exhibited enhanced ex vivo proliferation ability as compared to that before chemotherapy. In addition, platinum and fluorouracil also promoted the differentiation of human T cells into Th1 and Th9 subtypes and cytotoxic T lymphocytes (CTLs) in vitro and in vivo. Accordingly, the combination therapy greatly suppressed tumor growth with increased tumor infiltration of Th1, Th9, and CTL cells in a mouse tumor model. Moreover, in activated T cells, long-term treatment with these two drugs further facilitates T cell activation along with promoted nuclear factor-κB (NF-κB) activation. Our findings demonstrate a previously unidentified function of platinum and fluorouracil combination chemotherapy in promoting T cell–mediated antitumor immunity.

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A phase I study to evaluate the safety of multiantigen stimulated tumor specific cell therapy (MASCT-I) in subjects with advanced gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.200 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 200-200

Author(s):

Zhaode Bu ◽

Ziyu Jia ◽

Ke Ji ◽

Xin Ji ◽

Ji Zhang ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Cell Therapy ◽

Phase I ◽

Microsatellite Instability ◽

Advanced Gastric Cancer ◽

Immune Cell ◽

Gastroesophageal Junction ◽

Specific Cell

200 Background: Gastric cancer was the fifth cancer world wide and the third leading cause of cancer-related death. PD-1 antibody has been approved for treatment in gastric cancer patients with positive expression of PD-L1 and microsatellite instability. MASCT-I (Multi-Antigen Stimulated Cell Therapy-I Injection) is an autologous non-engineered immune cell therapy for solid tumor, it is composed of multiple-antigen peptides(15 tumor associated antigens) loaded mature dendritic cells (DCs) and in vitro DC stimulated and proliferated effector T cells, the combination of MASCT-I and PD1 antibody could have a synergistic anti-tumor effect. Methods: This is a single center, phase I trial to explore the safety and tolerance of the combination of MASCT-I and PD-1 antibody in advanced gastric cancer (NCT03393416). 15 patients with PD-L1 expression or microsatellite instability were enrolled between April 2018, and June 2019. Camrelizumab was administered once every two weeks, DC and T cells were sequential administered once a month. Therapy continued until the disease progresses. Results: Only adverse reaction below grade 2 was observed related to MASCT-I,such as fever, fatigue etc. Abnormal liver function and reactive capillary hyperplasia may be related to Camrelizumab. Among the 15 patients, the longest treatment duration was 18.9 months, and the median progression-free survival (mPFS) was 3.93 months, among which, mPFS of patients with microsatellite instability is 10.23 months, mPFS of patients expressing PD-L1 is 2.35 months, which is slightly higher than the historical data of Camrelizumab alone in the treatment of advanced gastric cancer (8 weeks for mPFS). The patient 1002 always had high content of CD8+ cells and NK cells and the positive immune response in their bodies, which may plays a role in killing the tumor cells. Conclusions: The combination of MASCT-I and Camrelizumab in the treatment of advanced gastric cancer or gastroesophageal junction cancer is a safe treatment regimen, and its efficacy deserves further study. Clinical trial information: NCT03393416.

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