“…Together with M0 macrophages and naïve CD4 T cells, γδ T cells contributed to an immune score that was superior to the classic TNM staging. 64 Fig. 3 How to enhance the efficacy of γδ T cell immunotherapy in vitro and in vivo.…”
Section: Tumor-infiltrating γδ T Cells: Friends or Foes?mentioning
γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional αβ T cells. Vγ9Vδ2 γδ T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. γδ T cells expressing other T cell receptor variable genes, notably Vδ1, are more abundant in mucosal tissue. In addition to the T cell receptor, γδ T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, γδ T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effector mechanisms, including cytokine production and cytotoxicity. In view of their HLA-independent potent antitumor activity, there has been increasing interest in translating the unique potential of γδ T cells into innovative cellular cancer immunotherapies. Here, we discuss recent developments to enhance the efficacy of γδ T cell-based immunotherapy. This includes strategies for in vivo activation and tumor-targeting of γδ T cells, the optimization of in vitro expansion protocols, and the development of gene-modified γδ T cells. It is equally important to consider potential synergisms with other therapeutic strategies, notably checkpoint inhibitors, chemotherapy, or the (local) activation of innate immunity.
“…Together with M0 macrophages and naïve CD4 T cells, γδ T cells contributed to an immune score that was superior to the classic TNM staging. 64 Fig. 3 How to enhance the efficacy of γδ T cell immunotherapy in vitro and in vivo.…”
Section: Tumor-infiltrating γδ T Cells: Friends or Foes?mentioning
γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional αβ T cells. Vγ9Vδ2 γδ T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. γδ T cells expressing other T cell receptor variable genes, notably Vδ1, are more abundant in mucosal tissue. In addition to the T cell receptor, γδ T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, γδ T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effector mechanisms, including cytokine production and cytotoxicity. In view of their HLA-independent potent antitumor activity, there has been increasing interest in translating the unique potential of γδ T cells into innovative cellular cancer immunotherapies. Here, we discuss recent developments to enhance the efficacy of γδ T cell-based immunotherapy. This includes strategies for in vivo activation and tumor-targeting of γδ T cells, the optimization of in vitro expansion protocols, and the development of gene-modified γδ T cells. It is equally important to consider potential synergisms with other therapeutic strategies, notably checkpoint inhibitors, chemotherapy, or the (local) activation of innate immunity.
“…8 In addition to reactive fibroblasts and M2 macrophages, the PDA microenvironment also contains γδ-T cells, which are a source of IFN-γ, and are associated with a poor prognosis. 9 We have previously shown that DNA vaccination that targets α-Enolase (ENO1), a tumor-associated antigen (TAA) that is upregulated in PDA, effectively prolongs survival in mice that spontaneously develop PDA. 10 This increased survival results from the induction of specific antibodies to ENO1 that activate complement-dependent cytotoxicity (CDC); a decrease in tumor infiltration by regulatory T cells and myeloid-derived suppressor cells Open access (MDSC); 11 inhibition of migration and invasion of PDA cells; 12 13 and an increase in tumor-infiltrating T cells 10 that relocalize into tertiary lymphoid tissue.…”
Section: Introductionmentioning
confidence: 99%
“… 8 In addition to reactive fibroblasts and M2 macrophages, the PDA microenvironment also contains γδ-T cells, which are a source of IFN-γ, and are associated with a poor prognosis. 9 …”
BackgroundPancreatic ductal adenocarcinoma (PDA) is an almost incurable tumor that is mostly resistant to chemotherapy (CT). Adaptive immune responses to tumor-associated antigens (TAA) have been reported, but immunotherapy (IT) clinical trials have not yet achieved any significant increase in survival, confirming the suppressive environment of PDA. As CT has immune-modulating properties, we investigated the effect of gemcitabine (GEM) in antitumor effector responses to TAA in patients with PDA.MethodsThe IgG antibody repertoire in patients with PDA before and after CT was profiled by serological proteome analysis and ELISA and their ability to activate complement-dependent cytotoxicity (CDC) was measured. Peripheral T cells were stimulated in vitro with recombinant TAA, and specific proliferation, IFN-γ/IL-10 and CD8+/Treg ratios were measured. Mice that spontaneously developed PDA were treated with GEM and inoculated with an ENO1 (α−Enolase) DNA vaccine. In some experimental groups, the effect of depleting CD4, CD8 and B cells by specific antibodies was also evaluated.ResultsCT increased the number of TAA recognized by IgG and their ability to activate CDC. Evaluation of the IFN-γ/IL-10 ratio and CD8+/Treg ratios revealed that CT treatment shifted T cell responses to ENO1, G3P (glyceraldheyde-3-phosphate dehydrogenase), K2C8 (keratin, type II cytoskeletal 8) and FUBP1 (far upstream binding protein 1), four of the most recognized TAA, from regulatory to effector. In PDA mice models, treatment with GEM prior to ENO1 DNA vaccination unleashed CD4 antitumor activity and strongly impaired tumor progression compared with mice that were vaccinated or GEM-treated alone.ConclusionsOverall, these data indicate that, in PDA, CT enhances immune responses to TAA and renders them suitable targets for IT.
“…Some studies have revealed the important role of these cells in cancer. For example, M2 macrophages were suppressors of anti-tumor immunity and gamma delta T cells were signi cantly correlated with an increased risk of death in pancreatic ductal adenocarcinoma [26,27]. Moreover, in ltration level of three immune cells including CD4 memory resting T cells, memory B cells and M2 macrophages were signi cantly correlated with expression of CTHRC1 and four immune cells contain CD4 memory resting T cells, memory B cells, eosinophils and gamma delta T cells were signi cantly related with expression of LRFN4.…”
Background
Stomach adenocarcinoma (STAD) is the most common histological type of stomach cancer, which causes a considerable number of deaths worldwide. This study specifically aimed to identify potential biomarkers and reveal the underlying molecular mechanisms.
Methods
Gene expression profiles microarray data were downloaded from the Gene Expression Omnibus (GEO) database. The ‘limma’ R package was used to screen the differentially expressed genes (DEGs) between STAD and matched normal tissues. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used for function enrichment analyses of DEGs. The data of STAD cases with both RNA sequencing and clinical information of The Cancer Genome Atlas (TCGA) were obtained from Genomic Data Commons (GDC) data portal. Survival curves were analyzed by the Kaplan-Meier method, univariate Cox regression analysis and multivariate Cox regression were performed using ‘survival’ package. CIBERSORT algorithm used approach to characterize the 22 human immune cell composition. Gene expression profiles microarray data and clinical information were downloaded from GEO database to validate prognostic model.
Results
Three public datasets including 90 STAD patients and 43 healthy controls were used and 44 genes were differentially expressed in all three datasets. These genes were primarily implicated in biological processes including cell adhesion, wound healing and extracellular matrix organization. Seven out of 44 genes showed significant survival differences based on their expression differences. CTHRC1 and LRFN4 were eventually used to constructed risk score and prognostic model by univariate Cox regression and stepwise multivariate Cox regression in The Cancer Genome Atlas (TCGA)-STAD dataset. The group having high risk scores and the group having low risk scores had significant differences in the infiltration level of multiple immune cells including CD4 memory resting T cells, M2 macrophages, memory B cells, resting dendritic cells, eosinophils, and gamma delta T cells. Multivariate Cox regression analyses indicated that the risk score was an independent predictor after adjusting for age, sex, and tumor stage. At last, the model was verified and evaluated by another independent dataset and showed a good classification effect.
Conclusions
The present study constructed the prognostic model by expression of CTHRC1 and LRFN4 for the first time via comprehensive bioinformatics analysis, which may provide clinical guidance and potential therapeutic targets for STAD.
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