Multiple lines of evidence have indicated that pro-inflammatory cytokines play a role in the pathophysiology of gastric carcinoma (GC).

To identify potential serum cytokine-based biomarkers for GC diagnosis.

The study cohort comprised 50 patients diagnosed with GC and 50 healthy control subjects. A panel of 7 pro-inflammatory cytokines, including interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-12, tumor necrosis factor-α, and interferon-γ (IFN-γ) were quantified using multiplex Luminex assays. Comparative analyses were conducted to evaluate cytokine levels between the GC patients and healthy controls. The diagnostic potential of serum pro-inflammatory cytokines in differentiating GC patients from healthy individuals was assessed through receiver operating characteristic (ROC) curve analysis. The correlation between serum cytokine levels and disease severity, as classified by the tumor-node-metastasis staging system, was analyzed using Spearman's rank correlation coefficient.

In comparison to the control group, patients with GC demonstrated significantly elevated serum levels of IL-1β (t = -4.089, P < 0.001), IL-6 (t = -3.983, P < 0.001), IL-8 (t = -5.460, P < 0.001), and IFN-γ (t = -2.856, P = 0.005). ROC curve analysis indicated that the area under the curve values for IL-1β, IL-6, and IL-8 exceeded 0.7, effectively distinguishing GC patients from healthy controls. Additionally, serum levels of IL-1β (r = 0.424, P = 0.012) and IL-6 (r = 0.742, P < 0.001) were positively correlated with the T stage in GC patients. Similarly, serum concentrations of IL-1β (r = 0.356, P = 0.039) and IL-6 (r = 0.441, P = 0.008) exhibited a positive association with the N stage in these patients.

These findings suggest that circulating pro-inflammatory cytokines, such as IL-1β, IL-6, and IL-8, may serve as potential biomarkers for the diagnosis of GC.

• Gastric carcinoma
• Pro-inflammatory cytokines
• Serum
• Biomarker
• Diagnosis

• Helicobacter pylori
• IL-17
• gastric cancer
• immunotherapy
• tumor microenvironment

• Stomach Neoplasms/immunology
• Humans
• Interleukin-17/metabolism
• Interleukin-17/immunology
• Animals
• Tumor Microenvironment/immunology
• Carcinogenesis/immunology

• National Natural Science Foundation of China

• cancer stem cell
• cancer-associated fibroblast
• epithelial-to-mesenchymal transition
• gastrointestinal tumor
• tumor heterogeneity
• tumor microenvironment

• Helicobacter pylori
• Interleukin 17
• gastric cancer
• gastritis

• Animals
• Helicobacter pylori/immunology
• Stomach Neoplasms/microbiology
• Stomach Neoplasms/genetics
• Stomach Neoplasms/immunology
• Helicobacter Infections/microbiology
• Helicobacter Infections/immunology
• Mice
• Interleukin-17/metabolism
• Interleukin-17/genetics
• Signal Transduction
• Receptors, Interleukin-17/metabolism
• Receptors, Interleukin-17/genetics
• Receptors, Interleukin-17/deficiency
• Mice, Transgenic
• Mice, Inbred C57BL
• Mice, Knockout
• Th17 Cells/immunology
• Gastritis/microbiology
• Gastritis/immunology

• I01 BX000915 BLRD VA
• IK2 BX005699 BLRD VA
• P30 DK058404 NIDDK NIH HHS
• R21 AI163586 NIAID NIH HHS

• gastric cancer
• overall survival
• prognostic signature
• rna-binding proteins

• Adult
• Aged
• Biomarkers, Tumor/genetics
• Female
• Humans
• Male
• Middle Aged
• Nomograms
• Prognosis
• RNA-Binding Proteins/genetics
• RNA-Binding Proteins/metabolism
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Survival Rate

• Gastric cancer
• immune cells
• immune-microenvironment
• immunotherapy
• tumor

Activation of NOTCH signaling pathways, which are key regulators of multiple cellular functions, has been frequently implicated in cancer pathogenesis, and NOTCH inhibitors have received much recent focus in the context of cancer therapeutics. However, the role and possible involvement of NOTCH pathways in stomach adenocarcinoma (STAD) are unclear. Here, putative regulatory mechanisms and functions of NOTCH pathways in STAD were investigated.

Publicly available data from the TCGA-STAD database were utilized to explore the involvement of canonical NOTCH pathways in STAD by analyzing RNA expression levels of NOTCH receptors, ligands, and downstream genes. Statistical analysis of the data pertaining to cancer and noncancerous samples was performed using R software packages and public databases/webservers.

Significant differential gene expression between control and STAD samples was noted for all NOTCH receptors (NOTCH1, 2, 3, and 4), the delta-like NOTCH ligands (DLL-3 and 4), and typical downstream genes (HES1 and HEY1). Four genes (NOTCH1, NOTCH2, NOTCH3, and HEY1) presented prognostic values for the STAD outcome in terms of overall survival. Functional enrichment analysis indicated that NOTCH family genes-strongly correlated genes were mainly enriched in several KEGG signaling pathways such as the PI3K-Akt signaling pathway, human papillomavirus infection, focal adhesion, Rap1 signaling pathway, and ECM-receptor interaction. Gene set enrichment analysis (GSEA) results showed that NOTCH family genes-significantly correlated genes were mainly enriched in four signaling pathways, ECM (extracellular matrix), tumor angiogenesis, inflammatory response, and immune regulation.

NOTCH family genes may play an essential role in the progression of STAD by modulating immune cells and mediating ECM synthesis, angiogenesis, focal adhesion, and PI3K-Akt signaling. Multiple NOTCH family genes are valuable candidate biomarkers or therapeutic targets for the management of STAD.

• Cancer
• Immune response
• Interleukin-17
• Pathophysiology
• Th17 cells
• Tumor microenvironment

• Cancer microenvironment
• Cancer stem cells
• Cancer-associated immune cells
• Cell reprogramming
• Gastric cancer
• Immunoregulation
• Immunotherapy

• Antineoplastic Agents/pharmacology
• Humans
• Immunotherapy
• Neoplastic Stem Cells
• Signal Transduction
• Stomach Neoplasms/therapy
• Tumor Microenvironment

• Consejo Nacional de Ciencia y Tecnología

• Humans
• Immunotherapy/methods
• Stomach Neoplasms/drug therapy
• Tumor Microenvironment

• P20 GM103395 NIGMS NIH HHS

• IFN-γ
• JAK/STAT signaling pathway
• Ovarian cancer
• SOCS1

Gastric cancer (GC) still represents the third leading cause of cancer-related death worldwide. Peritoneal relapse (PR) is the most frequent metastasis occurring among patients with advanced gastric cancer. Increasingly more evidence have clarified the tumor immune microenvironment (TIME) may predict survival and have clinical significance in GC. However, tumor-transcriptomics based immune signatures derived from immune profiling have not been established for predicting the peritoneal recurrence of the advanced GC.

In this study, we depict the immune landscape of GC by using transcriptome profiling and clinical characteristics retrieved from GSE62254 of Gene Expression Omnibus (GEO). Immune cell infiltration score was evaluated via single-sample gene set enrichment (ssGSEA) analysis algorithm. The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used to select the valuable immune cells and construct the final model for the prediction of PR. The receiver operating characteristic (ROC) curve and the Kaplan-Meier curve were used to check the accuracy of PRIs. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to explore the molecular pathways associated with PRIs.

A peritoneal recurrence related immune score (PRIs) with 10 immune cells was constructed. Compared to the low-PRIs group, the high-PRIs group had a greater risk. The upregulation of the focal adhesion signaling was observed in the high-PRIs subtype by GSEA and KEGG. Multivariate analysis found that both in the internal training cohort and the internal validation cohort, PRIs was a stable and independent predictor for PR. A nomogram that integrated clinicopathological features and PRIs to predict peritoneal relapse was constructed. Subgroup analysis indicated that the PRIs could obviously distinguish peritoneal recurrence in different molecular subtypes, pathological stages and Lauren subtypes, in which PRIs of Epithelial-Mesenchymal Transitions (EMT) subtype, III-IV stage and diffuse subtype are higher respectively.

Overall, we performed a comprehensive evaluation of the immune landscape of GC and constructed a predictive PR model based on the immune cell infiltration. The PRIs represents novel promising feature of predicting peritoneal recurrence of GC and sheds light on the improvement of the personalized management of GC patients after surgery.

• LASSO
• TME
• gastric cancer
• immune signature
• peritoneal relapse

Gastrosphere, an enriched cellular population with stem-like properties believed to be responsible for an escape from immune-mediated destruction. Th17 and Treg cells play a major role in gastric cancer; however, their interaction with gastrospheres remained elusive.

Peripheral blood mononuclear cells were isolated from healthy donors and were cultured with conditioned media of MKN-45 (parental) cells as well as gastrospheres' conditioned media in the context of mixed lymphocyte reaction and in the presence of anti-CD3/CD28 beads. The proliferation was evaluated using CFSE staining; the percentages of CD4⁺CD25⁺FoxP3⁺ Treg and CD4⁺IL-17⁺ Th17 cells and IFN-γ+cells and the production of IL-17, TGF-β, and IL-10 were assessed by flow cytometry and ELISA, respectively. Finally, the cytotoxic potential of induced immune cells was measured by examining the secretion of lactate dehydrogenase from target cells.

The results revealed a decreased expansion of PBMCs postexposure to gastrospheres' conditioned medium which was concomitant with an increased percentage of Th17 and an enhanced Th17 to Treg ratio. The conditioned media of gastrospheres enhanced the secretion of IL-10 and IL-17 and decreased TGF-β. Interestingly, immune cells induced by gastrospheres showed significant cytotoxicity in terms of producing IFN-γ and death induction in target cells. All these changes were related to the upregulation of IL-6, IL-10, and IL-22 in gastrospheres compared to parental cells.

Our study showed that the condition media of gastrospheres can potentially induce Th17 with increasing in their cytotoxic effect. Based on our knowledge, the present study is the first study that emphasizes the role of gastrospheres in the induction of antitumor Th17 cells. However, it should be confirmed with complementary studies in vivo.

• Cytokine modulation
• Human Th17
• T-cell plasticity
• inflammation

The single nucleotide polymorphisms of interleukin-21 (IL-21) gene were confirmed to be related to various diseases, but no studies have examined the possible role of IL-21 single nucleotide polymorphisms (SNPs) (rs907715, rs2221903, and rs12508721) in gastric precancerous lesions.

To explore the associations between SNPs of IL-21 gene (rs907715, rs2221903, and rs12508721) and gastric precancerous lesions in a Chinese population.

Three SNPs of IL-21 were genotyped using polymerase chain reaction–ligase detection reaction in 588 cases and 290 healthy controls from May 2013 to December 2016 in northwestern China. Gastric precancerous lesions were confirmed by endoscopic examination and categorized as non-atrophic gastritis, atrophic gastritis, and intestinal metaplasia. Descriptive statistic and logistic regression were used for data analyses.

IL-21 rs907715 genotype CC and C frequencies were higher in in patients with gastric precancerous lesions than in the controls (OR = 1.59, 95%CI: 1.06-2.38, P = 0.013; OR = 1.28, 95%CI: 1.01-2.22, P = 0.044, respectively) after adjusting for confounding factors. For SNP rs907715 in intestinal metaplasia patients, significant differences between cases and controls were observed in the frequencies of genotype CC and C (OR = 1.92, 95%CI: 1.24-2.98, P = 0.004; OR = 1.53, 95%CI: 1.04-2.24, P = 0.028, respectively); for non-atrophic gastritis and atrophic gastritis patients, the CC and C genotypes showed no significant association with risk in all models. No association between either rs2221903 or rs12508721 and gastric precancerous lesions was found in the present study. In the haplotype analysis, the TC haplotype (rs907715 and rs12508721) and TT haplotype (rs2221903 and rs907715) were more frequent in the case group than control group (P < 0.05).

Our findings indicate that SNP rs907715 of IL-21 gene is associated with gastric precancerous lesions. The TC haplotype (rs907715 and rs12508721) and TT haplotype (rs2221903 and rs907715) increased the risk of gastric precancerous lesions. If confirmed, these findings will shed light on the etiology of precancerous lesions.

• Interleukin-21 gene
• Single nucleotide polymorphisms
• rs907715
• Gastric precancerous lesions
• Intestinal metaplasia

• IL-17-producing γδT cells
• Migration
• Neuroblastoma
• Proliferation

• JNA
• cofilin
• disease-free survival
• immunohistochemistry
• juvenile nasopharyngeal angiofibroma
• prognosis
• recurrence

The aim of this study was to explore the correlation of chemokine receptor CXCR3 with M2 macrophage infiltration, various clinicopathological features, and prognosis in patients diagnosed with gastric cancer (GC).

Expression of CXCR3 protein and M2 macrophage was evaluated in 156 GC patients and corresponding paracancerous tissues by immunohistochemical (IHC) analysis.

In our study, 59 (37.82%) showed high expression of CXCR3 protein in 156 GC tissues. Expression of CXCR3 protein was significantly increased in tumor tissues compared with corresponding paracancerous tissues (P < 0.001). Overexpression of CXCR3 protein correlated with decreased M2 macrophage infiltration (P = 0.001). By analyzing the association between expression of CXCR3 protein and clinicopathological factors of GC patients, we found that high level of CXCR3 protein was significantly correlated with better differentiation (P =0.017), I/II TNM stage (P = 0.02), and smaller invasion depth (P = 0.003). Moreover, we found through Kaplan-Meier analysis and log-rank test that GC patients with high expression of CXCR3 protein and low M2 macrophage infiltration had better overall survival (OS) and low mortality rate (P < 0.001 and P = 0.024, respectively). The multivariate survival analysis showed that high expression of CXCR3 protein could serve as a favorable independent biomarker for prognosis in GC patients [hazard ratio (HR): 0.342 (0.204-0.571); P < 0.001].

Our study indicates that overexpression of CXCR3 protein in GC is associated with decreased M2 macrophage infiltration and improved OS and thus can be further exploited as a biomarker in GC.

• Notch signaling
• T helper 17 cells
• gastric cancer
• regulatory T cells

• Gastric cancer
• Gastritis
• Helicobacter pylori
• Peptic ulcer disease
• Th1

• Gastric Mucosa/immunology
• Gastric Mucosa/microbiology
• Gastric Mucosa/pathology
• Gastritis/immunology
• Gastritis/microbiology
• Gastritis/pathology
• Helicobacter Infections/immunology
• Helicobacter Infections/microbiology
• Helicobacter Infections/pathology
• Helicobacter pylori/immunology
• Helicobacter pylori/pathogenicity
• Host-Pathogen Interactions/immunology
• Humans
• Interferon-gamma/immunology
• Peptic Ulcer/microbiology
• Stomach Neoplasms/microbiology
• T-Lymphocytes, Regulatory/immunology
• Th1 Cells/immunology
• Th17 Cells/immunology

• chemokine C-X-C ligand 13
• circulating
• follicular helper T cells
• gastric cancer
• interleukin-21

• Gastric cancer
• IL-17A
• IL-17F
• Meta-analysis
• Polymorphisms

• Asian People/genetics
• Case-Control Studies
• Female
• Gene Frequency
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• Interleukin-17/genetics
• Interleukin-17/metabolism
• Male
• Odds Ratio
• Polymorphism, Single Nucleotide
• Risk Factors
• Stomach Neoplasms/genetics

• Angiogenesis
• Anti-tumor
• IL-17 cytokine
• Pro-tumor
• Th17 cells

• Adult
• Aged
• Binding Sites
• Female
• Genetic Predisposition to Disease/genetics
• Genotype
• Humans
• Interleukin-23/metabolism
• Male
• MicroRNAs/genetics
• Middle Aged
• Polymorphism, Single Nucleotide/genetics
• Stomach Neoplasms/genetics
• Th17 Cells/metabolism

Background: TFF1 deficiency induces a mucosal pro-inflammatory phenotype that contributes to gastric tumorigenesis in mouse and human. Methods: We utilized the Tff1-KO mouse model to assess the impact of TFF1 loss on immune cells infiltration in the stomach. We used single cell suspension, flow cytometry, immunohistochemistry, and quantitative PCR (qPCR) assays. Results: The Tff1-KO gastric mucosa demonstrated high chronic inflammatory scores (score: 3-4) at age 2 months, which exacerbated at age 8 months (score: 4-6). We next used single-cell suspensions for flow cytometry analysis of total leukocytes (CD45+ cells), total T lymphocytes (CD45+CD3+cells), T cell subsets (CD4+, CD8+, and CD3+CD4-CD8-cells), and monocytes/macrophages (CD45+F4/80+cells). The results demonstrated an age-dependent (2 → 8 month age) significant increase of leukocytes (p<0.05), T cells (p<0.05), and monocytes/macrophages (p<0.001) in the gastric mucosa of the Tff1-KO mice, as compared to Tff1-WT. A similar increase was observed in blood samples (p<0.05). Using ionomycin to activate CD4⁺ splenocytes, the results indicated that Tff1-KO CD4⁺ splenocytes secreted higher levels of IL-17A (p<0.05 at 2 and p<0.001 at 8 months) and IL-17F (p<0.05 at 2 and 8 months) than Tff1-WT splenocytes. Conversely, Tff1-KO CD8⁺-cells secreted less IL-17F, but comparable levels of IL-17A. In addition, we detected a significant upregulation of Il-17 mRNA expression in gastric tissues in the Tff1-KO, as compared to Tff1-WT (p<0.001). Conclusions: The results identify TFF1 loss as a major pro-inflammatory step that modulates the tumor microenvironment and immune cell infiltration in the stomach. Furthermore, the data suggest that the increase of IL-17A and IL-17F in Th17 cells, derived from CD4⁺ T cells, reflects the chronic inflammation in gastric mucosa, whereas the absence of change of IL-17A and decrease of IL-17F in CD8⁺Tc17 cells suggest loss of cytotoxic function of CD8⁺Tc17 cells during gastric tumorigenesis of the Tff1-KO mice.

• CD8
• Il-17
• Immune cells
• TFF1
• gastric cancer.
• lymphocytes

• NSCLC
• Th subset
• prognosis
• tumor microenvironment

• Adult
• Aged
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/pathology
• Female
• Flow Cytometry
• Humans
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Lymphocyte Count
• Lymphocytes, Tumor-Infiltrating/metabolism
• Male
• Middle Aged
• Prognosis
• Survival Analysis
• Th1 Cells/metabolism
• Th17 Cells/metabolism
• Th2 Cells/metabolism
• Tumor Microenvironment

Recently there has been heightened interest in the potential significance of interleukin (IL)-17 and IL-23 in the development/progression of human malignancies. Here, we analyzed the systemic levels of these cytokines in 75 patients with different types of gastric neoplasms (carcinoma, gastrointestinal stromal tumors, neuroendocrine neoplasms, and lymphomas) and 42 healthy volunteers. We found that patients with all types of gastric neoplasms have significantly lower IL-23 levels. However, in comparison to the levels in healthy individuals, IL-17 concentrations were lower only in patients with types of gastric neoplasms other than carcinoma. Interestingly, IL-17 levels significantly differed between patients with early and advanced gastric carcinoma. No significant associations were detected between the systemic levels of examined interleukins and TNM staging. However, peripheral levels of IL-23 were correlated with the absolute numbers of circulating populations of bone marrow-derived mesenchymal and very small embryonic/epiblast-like stem cells in patients with gastric carcinoma. ROC curve analyses demonstrated that systemic levels of IL-17 seem to meet basic criteria for consideration as a helpful diagnostic marker in the detection of gastric carcinoma. In conclusion, our study provides translational evidence confirming the clinical significance of IL-17 and IL-23 in the pathogenesis of different types of gastric neoplasms in humans.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China, and it is characterized by high malignancy, rapid progression, and easy metastasis. Current treatment options include liver transplantation, surgical resection and local ablative therapy. However, for all except transplantation, tumor recurrence rates are up to 70% after 5 years. In recent years, due to unsatisfying therapeutic effects of conventional therapies, the immune therapy of HCC has gradually become a hot research area. However, there exists a severe tumor immune microenvironment in HCC, which affects the immune therapeutic effects. Regulatory T (Treg) cells and T helper 17 (Th17) cells are two newly discovered subsets of CD4⁺ T cells. They play crucial roles in the maintenance of immune homeostasis and antitumor immunity, and they are important in forming microenvironmental immune suppression in HCC. Immunotherapy targeting Th17 or Treg cells in HCC appears to have potential feasibility. More evidence show that clarification of Th17/Treg balance and imbalance mechanisms may provide a new strategy for the immunotherapy of HCC.

• T helper 17 cells
• Regulatory T cells
• Hepatocellular carcinoma
• Therapy

Gastric cancer (GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori (H. pylori). Infection with H. pylori leads to an active inflammatory microenvironment that is maintained by immune cells such as T cells, macrophages, natural killer cells, among other cells. Immune cell dysfunction allows the initiation and accumulation of mutations in GC cells, inducing aberrant proliferation and protection from apoptosis. Meanwhile, immune cells can secrete certain signals, including cytokines, and chemokines, to alter intracellular signaling pathways in GC cells. Thus, GC cells obtain the ability to metastasize to lymph nodes by undergoing the epithelial-mesenchymal transition (EMT), whereby epithelial cells lose their epithelial attributes and acquire a mesenchymal cell phenotype. Metastasis is a leading cause of death for GC patients, and the involved mechanisms are still under investigation. In this review, we summarize the current research on how the inflammatory environment affects GC initiation and metastasis via EMT.

• Gastric cancer
• Inflammation
• Epithelial-mesenchymal transition
• Microenvironment
• Immune cells

• Epithelial-Mesenchymal Transition
• Humans
• Inflammation/pathology
• Macrophages/immunology
• Neoplasm Metastasis
• Stomach Neoplasms/immunology
• Stomach Neoplasms/pathology
• T-Lymphocytes, Cytotoxic/immunology
• Transforming Growth Factor beta1/physiology

• T-helper 1
• T-helper 17
• T-helper 2
• cytokine
• laryngeal carcinoma

• Correlation analysis
• Entropy
• Gene Ontology
• Gene expression
• Principal component analysis
• RNA-seq
• T-cell differentiation
• Transcriptomics

• Carcinogenesis/genetics
• China
• Genetic Predisposition to Disease/genetics
• Humans
• Interleukin-17/genetics
• Polymorphism, Single Nucleotide/genetics
• Risk Factors
• Stomach Neoplasms/genetics

• Humans
• Interleukin-17/metabolism
• Neoplasm Metastasis/physiopathology
• Neoplasms/metabolism
• Neovascularization, Pathologic

• IL-17A
• RORγt
• Th17
• cancer
• immunotherapy
• plasticity
• tumor microenvironment

Excessive immune responses directed against foreign pathogens, self-antigens, or commensal microflora can cause cancer establishment and progression if the execution of tight immuno-regulatory mechanisms fails. On the other hand, induction of potent tumor antigen-specific immune responses together with stimulation of the innate immune system is a pre-requisite for effective anti-tumor immunity, and if suppressed by the strong immuno-regulatory mechanisms can lead to cancer progression. Therefore, it is crucial that the inevitable co-existence of these fundamental, yet conflicting roles of immune-regulatory cells is carefully streamlined as imbalances can be detrimental to the host. Infection with chronic persistent viruses is characterized by severe immune dysfunction resulting in T cell exhaustion and sometimes deletion of antigen-specific T cells. More often, this is due to increased immuno-regulatory processes, which are triggered to down-regulate immune responses and limit immunopathology. However, such heightened levels of immune disruption cause a concomitant loss of tumor immune-surveillance and create a permissive microenvironment for cancer establishment and progression, as demonstrated by increased incidences of cancer in immunosuppressed hosts. Paradoxically, while some cancers arise as a consequence of increased immuno-regulatory mechanisms that inhibit protective immune responses and impinge on tumor surveillance, other cancers arise due to impaired immuno-regulatory mechanisms and failure to limit pathogenic inflammatory responses. This intricate complexity, where immuno-regulatory cells can be beneficial in certain immune settings but detrimental in other settings underscores the need for carefully formulated interventions to equilibrate the balance between immuno-stimulatory and immuno-regulatory processes.

• HIV-1
• cancer
• immune dysfunction
• immune-regulation
• inflammation
• regulatory T cells