Na Zhao

DNA sensor proteins play an important role in transducing DNA signals to induce immune responses that initiate inflammation or clear pathogens. It has been previously shown that several DNA sensors are involved in regulating tumor biology and/or cancer immunology. However, a systemic analysis of DNA sensor expression and its correlation with prognosis has not been conducted. Here, we analyzed messenger RNA expression and protein abundance in liver cancer databases and found that the genes of 5 DNA sensors (POLR3A, PRKDC, DHX9, cGAS, and MRE11) were consistently upregulated in tumor tissue. Moreover, the expression of these DNA sensor genes correlated with patient survival. Using a gene alterations analysis, we discovered that patients with genetically altered DNA sensors had significantly lower survival compared with an unaltered group. Furthermore, receiver-operating characteristic curves confirmed that the signatures of the 5 DNA sensors were independent prognostic factors in hepatocellular carcinoma. Tumor-infiltrating immune cell analysis revealed that expression of all 5 DNA sensors correlated with the amount of B cells, CD8 T cells, CD4 T cells, Tregs, DCs, Mϕs, and neutrophils. Surprisingly, 4 of the DNA sensors (POLR3A, PRKDC, DHX9, and MRE11) were inversely correlated with the amount of γδ T cells. Gene set enrichment analysis showed that all 5 DNA sensor genes were enriched for oxidative phosphorylation and xenobiotic metabolism. These results suggest that expression of these DNA sensors is associated with a unique immune profile and metabolic regulation in hepatocellular carcinoma.

Butyrophilins (BTNs) belong to the immunoglobulin superfamily of transmembrane proteins and play a role in the regulation of lymphocyte activation, several autoimmune diseases, and the progression of human cancers. However, the associated clinicopathologic characteristics and prognostic value of BTNs in breast cancer remain unknown. This study aimed to discover potential key related BTN genes and signaling pathways in breast cancer, which could provide new insights for immune-based strategies. In the present study, the mRNA expression level and prognostic value of BTN2A1, BTN3A1, BTN3A2, BTN3A3, BTNL2, BTNL9, ERMAP, and MOG were measured. Up-regulation of these genes was significantly correlated with improved overall and relapse-free survival. We then analyzed the prognostic outcomes of breast cancer subtypes, genetic alterations, interaction networks, and the functional enrichment of eight BTN family genes. Our results showed that these eight genes played essential roles in tumor progression. Furthermore, an immune infiltration analysis indicated that most candidate BTN family members were associated with intratumoral immune cell infiltration, especially that of γδ T cells. Finally, gene set enrichment analysis for a single hub gene revealed that each BTN gene played a vital role in tumor progression through immune signaling pathways. These findings provided new insights into breast cancer pathogenesis and identified eight potential biomarkers for breast cancer.

Background Hepatic inflammatory response is a risk factor for liver cancer initiation and progression. Interleukin (IL)‐35 is the newest member of IL‐12 cytokine family, and has been reported to play an essential role in the immunosuppressive liver microenvironment. Herein we focus on the expression profiles of IL‐35 in hepatocellular carcinoma (HCC) and effects on local immune status. Methods HCC transcriptome array data were downloaded from GEO. Analysis was performed by BRB array tools and IPA software. Serum IL‐35 level was detected by AimPlet bead‐based immunoassay. In situ IL‐35 detection was performed by immunohistochemical staining and western blot. In vitro effect of IL‐35 on CD4⁺ or CD8⁺ T cell function was detected by flow cytometry. Results Our results showed that there were large amounts of IL‐35 expressed in HCC serum and tumor tissues. IL‐35 expression affects the transcript of thousands of genes, most differentially expressed genes (DEGs) in tumor tissues correlated with T‐cell immunity. The IL‐35 high‐expression group exhibited enhancement of regulatory T cells (Tregs) and impairment of cytolytic T cells. In vitro experiments proved that exogenous IL‐35 stimulated the expression of PD1 and LAG3 in CD4⁺ and CD8⁺ T cells. In addition, the stimulating effect was time‐dependent. Furthermore, IL‐35 inhibited interferon(IFN)‐γ secretion by CD4⁺ and CD8⁺ T cells. Conclusions Elevated IL‐35 had an immune suppressive role in HCC tumor microenvironments through affecting inhibitor receptor expression and cytokine secretion of CD4⁺ and CD8⁺ T cells. Dissection of the precise targets and underlying molecular mechanisms would mean alternative treatments for HCC patients. (250 words)

Background: Hashimoto’s thyroiditis (HT) is a common autoimmune disease, and an increasing number of papillary thyroid carcinoma (PTC) cases are being diagnosed in HT patients. The aim of this study was to investigate the proportion and function of different T cell subtypes in peripheral blood, especially CD4⁺Foxp3⁺ regulatory T cells (Tregs), in PTC with and without HT. We also studied the effect of HT on PTC. Methods: Flow cytometry was used to detect the proportions of CD4⁺ T cells, CD8⁺ T cells, CD4⁺Foxp3⁺ Tregs, and the level of interleukin-10 (IL-10) secreted by CD4⁺ T cells in the peripheral blood of PTC patients with and without HT. AimPlex bead-based immunoassays were used to determine serum cytokine levels. Results: No significant differences were observed in the proportion of CD4⁺ or CD8⁺ T cells in the two groups of PTC patients. The percentage of CD4⁺FoxP3⁺ Tregs and their levels of IL-10 were significantly lower in PTC patients with HT than in those without HT. Conclusions: Our findings suggest that CD4⁺Foxp3⁺ Tregs have vital regulatory functions in the initiation and progression of PTC by secreting the inhibitory cytokine IL-10.

Inducing donor-specific immunological tolerance, which avoids the complications of long-term immunosuppression, is an important goal in organ transplantation. Interleukin-35 (IL-35), a cytokine identified in 2007, is mainly secreted by regulatory T cells (Tregs) and is essential for Tregs to exert their maximal immunoregulatory activity in vitro and in vivo. A growing number of studies show that IL-35 plays an important role in autoimmune diseases and infectious diseases. Recent research has shown that IL-35 could effectively alleviate allograft rejection and has the potential to be a novel therapeutic strategy for graft rejection. With increasing study of immunoregulation, cell-based therapy has become a novel approach to attenuate rejection after transplantation. Mesenchymal stem cells (MSCs), which exhibit important properties of multilineage differentiation, tissue repair, and immunoregulation, have recently emerged as attractive candidates for cell-based therapeutics, especially in transplantation. Accumulating evidence demonstrates that the therapeutic abilities of MSCs can be amplified by gene modification. Therefore, researchers have constructed IL-35 gene-modified MSCs and explored their functions and mechanisms in some disease models. In this review, we discuss the potential tolerance-inducing effects of MSCs in transplantation and briefly introduce the immunoregulatory functions of the IL-35 gene-modified MSCs.