Morphine and ketamine inhibit immune function of gastric cancer patients by increasing percentage of CD4 + CD25 + Foxp3 + regulatory T cells in vitro

Elucidating mechanisms involved in tumor-induced immunosuppression is of great interest since it could help to improve cancer immunotherapy efficacy. Here we show that Hepatocyte Growth Factor (HGF), a pro-tumoral and proangiogenic factor, and its receptor c-Met are involved in regulatory T cells (Treg) accumulation in the peripheral blood of gastric cancer (GC) patients. We observed that c-Met is expressed on circulating monocytes from GC patients. The elevated expression on monocytes is associated with clinical parameters linked to an aggressive disease phenotype and correlates with a worse prognosis. Monocyte-derived dendritic cells from GC patients differentiated in the presence of HGF adopt a regulatory phenotype with a lower expression of co-stimulatory molecules, impaired maturation capacities, and an increased ability to produce interleukin-10 and to induce Treg differentiation in vitro. In the MEGA-ACCORD20-PRODIGE17 trial, GC patients received an anti-HGF antibody treatment (rilotumumab), which had been described to have an anti-angiogenic activity by decreasing proliferation of endothelial cells and tube formation. Rilotumumab decreased circulating Treg in GC patients. Thus, we identified that HGF indirectly triggers Treg accumulation via c-Met-expressing monocytes in the peripheral blood of GC patients. Our study provides arguments for potential alternative use of HGF/c-Met targeted therapies based on their immunomodulatory properties which could lead to the development of new therapeutic associations in cancer patients, for example with immune checkpoint inhibitors.

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Effect of andecaliximab (anti-MMP9) on proteolysis of IL-7 in vitro, TCR diversity in mice, and serum IL-7 in gastric cancer patients in combination with chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.101 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 101-101 ◽

Cited By ~ 1

Author(s):

Andrew E. Greenstein ◽

Marianna Zavodovskaya ◽

Maile Velasquez ◽

Perry Weissburg ◽

Vladi Juric ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Tumor Model ◽

Mouse Tumor ◽

Gastric Cancer Study ◽

Tcr Diversity ◽

Folded Proteins ◽

Gastric Cancer Patients

101 Background: Andecaliximab (andeca) is a monoclonal antibody that selectively inhibits matrix metalloproteinase 9 (MMP9). IL-7 selectively enhances the proliferation and survival of naïve, memory, and effector T-cells (but not regulatory T-cells) in the periphery. Previous clinical trials with systemic recombinant IL-7 therapy increased TCR diversity. In the disease setting, elevated circulating IL-7 may be due to a compensatory increase in IL-7 production as demonstrated in mice upon inhibition of IL-7 signaling. Methods: An in vitro screen, in which recombinant active human MMP9 was incubated with > 140 human recombinant folded proteins, identified IL-7 as the most efficient substrate of MMP9. Results: IL-7 proteolysis occurred between A128:L129. IL-7 proteolysis altered the global protein structure, evidenced by a loss of cooperative unfolding observed with intact IL-7 (intrinsic fluorescence, Tm = 59.3o C). Mouse MMP9 proteolyzed mouse IL-7 in vitro. In the orthotopic syngeneic NeuT mouse model, MMP9 inhibition reduced tumor growth (p = 0.0005). In a 7-day NeuT study, anti-MMP9 alone improved TCR diversity (decreased clonality) within tumor-infiltrating T-cells (Dunnett’s p = 0.0083). Further, anti-MMP9 and anti-PDL1 co-treatment promoted an increase in CD3+ cells (p = 0.01), CD4+ T cells (p = 0.006), and CD8+ T cells (p = 0.013) concomitant with a decrease in tumor-associated CD25+ FoxP3+ regulatory T cells (p = 0.04) in the tumor. In gastric cancer patient serum, pro-MMP9 (p < 0.0001), active MMP9 (p < 0.0001), and IL-7 (p < 0.0001) were higher than healthy controls. Serum IL-7 levels were normalized upon treatment with andeca plus mFOLFOX6 (N = 40; FDR-corrected p < 0.001) in a Phase I gastric cancer study. Conclusions: MMP9 proteolyzed IL-7 in vitro. Specific MMP9 inhibition in a mouse tumor model improved TCR diversity. Andeca +mFOLFOX6 therapy normalized serum IL-7 levels, which could be due to andeca, chemotherapy, or disease resolution. The functional implications of IL-7 proteolysis by MMP9 in gastric cancer are currently under investigation.

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ILDR1 Is a Prognostic Biomarker and Associated With Immune Inﬁltration in Gastric Cancer

10.21203/rs.3.rs-944596/v1 ◽

2021 ◽

Author(s):

Yanling Ma ◽

WenBo Qi ◽

BaoHong Gu ◽

XueMei Li ◽

ZhenYu Yin ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Dendritic Cells ◽

Cancer Patients ◽

Cd8 T Cells ◽

Immune Cells ◽

Copy Number ◽

Sequencing Data ◽

Number Variation ◽

Gastric Cancer Patients

Abstract Objective: To investigate the association between ILDR1 and prognosis and immune infiltration in gastric cancer. Methods: We analyzed the RNA sequencing data of 9736 tumor tissues and 8587 normal tissues in the TCGA and GTEx databases through the GEPIA2 platform. The expression of ILDR1 in gastric cancer and normal gastric mucosa tissues with GEPIA and TIMER. Clinical subgroup analysis was made through Kaplan-Meier analysis. Analyzed the correlation between ILDR1 and VEGFA expression in gastric cancer, through the gene sequencing data of gastric cancer in TCGA. Explored the relationship between ILDR1 methylation and the prognosis of gastric cancer patients through the MethSurv database. The correlation between ILDR1 and immune cells and the correlation of copy number variation were explored through the TIMER database. Results: ILDR1-high GC patients had a lower PFS and OS. High ILDR1 expression was significantly correlated with tumor grade. There was a negative correlation between the ILDR1 expression and the abundances of CD8+ T, Macrophages and DC and etc. The methylation level of ILDR1 is associated with a good prognosis of gastric cancer. ILDR1 copy number variation was correlated with immune cells, IDLR1 arm-loss was associated with the infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells, and arm-duplication was associated with the infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells. Conclusion: The increased expression of ILDR1 is associated with poor prognosis in patients with gastric cancer. ILDR1 can be used as a novel predictive biomarker to provide a new therapeutic target for gastric cancer patients.

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Pleckstrin-2 as a Prognostic Factor and Mediator of Gastric Cancer Progression

Gastroenterology Research and Practice ◽

10.1155/2021/5527387 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Jun Wang ◽

Zhigang He ◽

Bo Sun ◽

Wenhai Huang ◽

Jianbin Xiang ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Patients ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

In Vivo Studies ◽

Vimentin Expression ◽

Mesenchymal Transition ◽

Gastric Cancer Patients

Pleckstrin-2 (PLEK2) is a crucial mediator of cytoskeletal reorganization. However, the potential roles of PLEK2 in gastric cancer are still unknown. PLEK2 expression in gastric cancer was examined by western blotting and real-time PCR. Survival analysis was utilized to test the clinical impacts of the levels of PLEK2 in gastric cancer patients. In vitro and in vivo studies were used to estimate the potential roles played by PLEK2 in modulating gastric cancer proliferation, self-renewal, and tumourigenicity. Bioinformatics approaches were used to monitor the effect of PLEK2 on epithelial-mesenchymal transition (EMT) signalling pathways. PLEK2 expression was significantly upregulated in gastric cancer as compared with nontumour samples. Kaplan-Meier plotter analysis revealed that gastric cancer patients with higher PLEK2 levels had substantially poorer overall survival compared with gastric cancer patients with lower PLEK2 levels. The upregulation or downregulation of PLEK2 in gastric cancer cell lines effectively enhanced or inhibited cell proliferation and proinvasive behaviour, respectively. Additionally, we also found that PLEK2 enhanced EMT through downregulating E-cadherin expression and upregulating Vimentin expression. Our findings demonstrated that PLEK2 plays a potential role in gastric cancer and may be a novel therapeutic target for gastric cancer.

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Abstract 4094: Identification of co-inhibitory receptor expression on T cells from gastric cancer patients

10.1158/1538-7445.am2014-4094 ◽

2014 ◽

Cited By ~ 1

Author(s):

Yunhui Zong ◽

Fuliang Chu ◽

Songbing He ◽

Yu Jing ◽

Sally A Hunsucker ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Cancer Patients ◽

Receptor Expression ◽

Inhibitory Receptor ◽

Gastric Cancer Patients

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Poor clinical outcomes and immunoevasive contexture in CXCL13+CD8+ T cells enriched gastric cancer patients

OncoImmunology ◽

10.1080/2162402x.2021.1915560 ◽

2021 ◽

Vol 10 (1) ◽

pp. 1915560

Author(s):

Kaifeng Jin ◽

Yifan Cao ◽

Yun Gu ◽

Hanji Fang ◽

Yuchao Fei ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Cancer Patients ◽

Clinical Outcomes ◽

Cd8 T Cells ◽

Gastric Cancer Patients

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Telomerase Activity and Telomere Length of CD4+CD25+ Regulatory T-Cells under Conditions of In Vitro and In Vivo Expansion.

Blood ◽

10.1182/blood.v104.11.3857.3857 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3857-3857

Author(s):

Dominik G.F. Wolf ◽

Anna M. Wolf ◽

Christian Koppelstaetter ◽

Holger F. Rumpold ◽

Gert Mayer ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Telomere Length ◽

Cancer Patients ◽

Telomerase Activity ◽

Telomere Maintenance ◽

Healthy Human ◽

Telomere Shortening

Abstract The expandability of CD4+CD25+ regulatory T-cells (Treg) has been shown in vitro and in vivo. Activation of telomerase activity is a prerequisite for clonal expansion and telomere maintenance in T-cells. There is currently no data available on the expression and function of telomerase in proliferating Treg. Analyses of telomere length by flow-FISH, real-time PCR and Southern blotting revealed that Treg isolated from healthy human volunteers have significantly shortened telomeres when compared to CD4+CD25− T-cells. However, telomere length is not further shortened in Treg isolated from the peripheral blood of cancer patients, despite the observation that the regulatory T-cell pool of these patients was significantly enlarged. To gain further insight into maintenance of telomere length of Treg, we induced in vitro proliferation of Treg by stimulation with anti-CD3 and IL-2. This led to a rapid increase of telomerase activity, as determined by PCR-ELISA. However, when we focused on the proliferating fraction of Treg using a sorting strategy based on the dilution of CFSE, we could show a significant telomere shortening in Treg with high proliferative and immmuno-suppressive capacity. Of note, proliferating CFSElow Treg are characterized by high telomerase activity, which however seems to be insufficient to avoid further telomere shortening under conditions of strong in vitro stimulation. In contrast, under conditions of in vivo expansion of Treg in cancer patients, the induction of telomerase activity is likely to compensate for further telomere erosion. These data might be of importance when considering the application of in vitro expanded Treg for the treatment of GvHD or autoimmune diseases, as telomere shortening might be associated with genomic instability.

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Maintenance of Telomere Length in Peripheral Blood CD4+CD25+ Regulatory T-Cells of Cancer Patients Despite Active Proliferation.

Blood ◽

10.1182/blood.v106.11.3309.3309 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3309-3309

Author(s):

Dominik Wolf ◽

Holger Rumpold ◽

Christian Koppelstaetter ◽

Guenther Gastl ◽

Eberhard Gunsilius ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Telomere Length ◽

Cancer Patients ◽

Peripheral Blood ◽

Telomerase Activity ◽

Telomere Shortening ◽

Active Proliferation

Abstract CD4+CD25+ regulatory T-cells (Treg) are increased in the peripheral blood of cancer patients. It remains unclear whether this is due to redistribution or active proliferation. The latter would require the up-regulation of telomerase activity, whose regulation also remains unknown for Treg. We therefore isolated Treg and the respective CD4+CD25− control T-cell population from peripheral blood of cancer patients (n=23) and healthy age-matched controls (n=17). Analysis of their content of T-cell receptor excision circles (TREC) revealed that the observed increase of Treg frequencies in peripheral blood is due to active cycling rather than to redistribution from other compartments (i.e. secondary lymphoid organs or bone-marrow), as Treg from cancer patients are characterized by a significant decrease of TREC content when compared to TREC content of Treg isolated from healthy age-matched controls. Surprisingly, despite their proven in vivo proliferation, telomere length is not further shortened in Treg from peripheral blood of cancer patients as shown by Flow-Fish, Real-Time PCR and Southern Blotting. Accodingly, telomerase activity of Treg was readily inducible in vitro by OKT3 together with IL-2. Notably, sorting of in vitro proliferating Treg using dilution of CFSE revealed a significant telomere shortening in Treg with high proliferative capacity (i.e. CFSElow fraction) under conditions of strong in vitro stimulatory growth conditions despite a high telomerase activity. Thus, under conditions of strong in vitro stimulation induction of telomerase seems to be insufficient to avoid progressive telomere shortening. In contrast, in actively proliferating peripheral blood Treg from patients with epithelial malignancies induction of telomerase activity is likely to compensate for further telomere erosion.

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