NK007 helps in mitigating paclitaxel resistance through p38MAPK activation and HK2 degradation in ovarian cancer.

Ovarian cancer resistance to available medicines is a huge challenge in dire need of a solution, which makes its recurrence and mortality rate further exacerbated. A promising approach to overcome chemoresistance is drug screening from natural products. Here, we report that NK007, a (±)-tylophorine malate isolated from the Asclepiadaceae family, selectively inhibited the proliferation of A2780 and A2780 (Taxol) cells and migration of paclitaxel-sensitive and -resistant ovarian cancer cells. Interestingly, the decline of cell viability, including cell multiplication, clonality, and migration capacity was independent on cell apoptosis. At the molecular level, NK007 considerably induced G1/S arrest and upregulated the expression of phospho-p38 mitogen-activated protein kinase (p-p38MAPK). In addition, hexokinase 2 (HK2) protein degradation was considerably elevated in the presence of NK007, which resulted in the reduction of oxygen consumption rate and extracellular acidification rate. Altogether, our results indicate that NK007, an analog of tylophorine, can overcome paclitaxel (PTX) resistance through p38MAPK activation and HK2 degradation. As an effective, alternative antiresistance agent, NK007 exhibits a promising potential to treat PTX-resistant ovarian cancer.

The use of distress thermometer in advanced cancer inpatients with pain.

OBJECTIVE: This study aimed to provide support for the extensive application of Distress Thermometer (DT) in advanced cancer inpatients with pain and explored factors associated with high DT scores among this population. METHODS: Advanced cancer patients with pain were recruited from Department of Pain Relief in Tianjin Cancer Hospital and Institute, China. They completed the DT with problems list and HADS within 48 h after admission. The cutoff score of DT was evaluated against Hospital Anxiety and Depression Scale (HADS) for its sensitivity and specificity by using receiver operating characteristic (ROC) curves. Multiple logistic regression model analysis was performed to investigate correlates of DT scores. RESULTS: Four hundred forty one inpatients with mixed diagnoses were recruited. Referring to the cutoff of 15 on HADS, DT cutoff score of 5 yielded AUC of 0.757, with an optimal sensitivity of 0.861 and specificity of 0.531. Using the cutoff scores of greater than or equal to 5, 70.5% of the patients were distressed. Logistic regression analysis of DT found that the breakthrough pain, poorer KPS, higher pain degree, and emotional problems were the predictive factor for current distress. CONCLUSION: DT is efficacious in screening for psychological distress in advanced cancer inpatients with pain. Psychological distress is prevalent with a cutoff score of greater than or equal to five. To better identify the distressed cancer patients with pain, pain degree, performance status, and emotional problems should be considered together.

miR-20b suppresses Th17 differentiation and the pathogenesis of experimental autoimmune encephalomyelitis by targeting RORγt and STAT3.

The differentiation and function of IL-17-producing Th17 cells are tightly regulated by specific transcription factors and cytokines, which are the key participants in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Although specific miRNAs have been shown to be involved in the development of MS and EAE, the potential role of miRNAs in the context of Th17-driven autoimmunity is just beginning to be clarified. miR-20b has been reported as a downregulated miRNA in blood cells of MS patients. In this report, it was further studied in greater detail because we found it was significantly downregulated during EAE, and, in the in vitro differentiation model, Th17 cells had lower expression of miR-20b than did Th1, Th2, or inducible T regulatory cells. Ectopic expression of miR-20b repressed Th17 differentiation in vitro. Using lentiviral vectors for miR-20b overexpression in vivo, we demonstrated that overexpression of miR-20b led to decreased Th17 cells and reduced severity of EAE. Furthermore, we also identified both RAR-related orphan receptor γt and STAT3 as potential targets of miR-20b. Finally, we confirmed that the mild disease severity and low number of Th17 cells in LV-miR-20b-infected mice were largely reversed by coinfection of these mice with lentivirus-expressing RAR-related orphan receptor γt or STAT3 3'-untranslated regions. Taken together, our results contribute to the importance of miRNAs in Th17 differentiation and pathogenesis of MS and EAE.

Critical role of dendritic cell-derived IL-27 in antitumor immunity through regulating the recruitment and activation of NK and NKT cells.

Critical roles of IL-27 in autoimmune diseases and infections have been reported; however, the contribution of endogenous IL-27 to tumor progression remains elusive. In this study, by using IL-27p28 conditional knockout mice, we demonstrate that IL-27 is critical in protective immune response against methyl-cholanthrene-induced fibrosarcoma and transplanted B16 melanoma, and dendritic cells (DCs) are the primary source. DC-derived IL-27 is required for shaping tumor microenvironment by inducing CXCL-10 expression in myeloid-derived suppressor cells and regulating IL-12 production from DCs, which lead to the recruitment and activation of NK and NKT cells resulting in immunological control of tumors. Indeed, reconstitution of IL-27 or CXCL-10 in tumor site significantly inhibits tumor growth and restores the number and activation of NK and NKT cells. In summary, our study identifies a previous unknown critical role of DC-derived IL-27 in NK and NKT cell-dependent antitumor immunity through shaping tumor microenvironment, and sheds light on developing novel therapeutic approaches based on IL-27.

High susceptibility to liver injury in IL-27 p28 conditional knockout mice involves intrinsic interferon-γ dysregulation of CD4+ T cells.

UNLABELLED: Interleukin (IL)-27, a newly discovered IL-12 family cytokine, is composed of p28 and EBI3. In this study, CD11c-p28(f/f) conditional knockout mice were generated to delete p28 specifically in dendritic cells (DCs). We demonstrated that in the absence of DC-derived p28, these mice were highly susceptible to both low and higher concentrations of concanavalin A (ConA) (5 mg/kg or 10 mg/kg), with extremely early and steady high levels of interferon-γ (IFN-γ) in sera. Neutralizing IFN-γ prevented ConA-induced liver damage in these mice, indicating a critical role of IFN-γ in this pathological process. Interestingly, the main source of the increased IFN-γ in CD11c-p28(f/f) mice was CD4+ T cells, but not natural killer T (NKT) cells. Depletion of CD4+ , but not NK1.1+ , cells completely abolished liver damage, whereas transferring CD4+ T cells from CD11c-p28(f/f) mice, but not from wild-type mice or CD11c-p28(f/f) -IFN-γ(-/-) double knockout mice to CD4(-/-) mice, restored the increased liver damage. Further studies defined higher levels of IFN-γ and T-bet messenger RNA in naïve CD4+ T cells from CD11c-p28(f/f) mice, and these CD4+ T cells were highly responsive to both low and higher concentrations of anti-CD3, indicating a programmed functional alternation of CD4+ T cells. CONCLUSION: We provide a unique model for studying the pathology of CD4+ T cell-mediated liver injury and reveal a novel function of DC-derived p28 on ConA-induced fulminant hepatitis through regulation of the intrinsic ability for IFN-γ production by CD4+ T cells.

Interactions between γδ T cells and neutrophils in cancer: knowns and unknowns.

The tumor microenvironment provides a unique opportunity to gain insight into the relationship and crosstalk between different cell types. In this context, little is known about the interaction between γδ T cells and neutrophils, which are innate immune cells abundant in the tumor microenvironment. Interestingly, both γδ T cells and neutrophils are heterogeneous, may play diverse regulatory roles, and have been shown to have both protumor and antitumor functions. In this editorial, we discuss recent advances in the understanding of interplay between γδ T cells and neutrophils in cancer and provide insights and future directions highlighting the role these interactions may play in cancer.

Tumor Immune Infiltration and Clinical Impact of Specific BCG-Related Genes in Melanoma.

Melanoma, caused by malignant melanocytes, is known for its invasiveness and poor prognosis. Therapies are often ineffective due to their heterogeneity and resistance. Bacillus Calmette-Guérin (BCG), primarily a tuberculosis vaccine, shows potential in treating melanoma by activating immune responses. In this study, data from The Cancer Genome Atlas and the NCBI GEO database were utilized to determine pivotal differentially expressed genes (DEGs) such as DSC2, CXCR1, BOK, and CSTB, which are significantly upregulated in BCG treated blood samples and are strongly associated with the prognosis of melanoma. We employ tools like edgeR and ggplot2 for functional and pathway analysis and develop a prognostic model using LASSO Cox regression analysis to predict patient survival. A notable finding is the correlation between BCG-related genes and immune cell infiltration in melanoma, highlighting the potential of these genes as both biomarkers and therapeutic targets. Additionally, the study examines genetic alterations in these genes and their impact on the disease. This study highlights the necessity of further exploring BCG-related genes for insights into melanoma pathogenesis and treatment enhancement, suggesting that BCG's role in immune activation could offer novel therapeutic avenues in cancer treatment.

A Comprehensively Prognostic and Immunological Analysis of PARP11 in Pan-cancer.

Poly (ADP ribose) polymerase family member 11(PARP11) has important immune regulatory functions in viral infection and tumor immune response. Particularly, PARP11 showed protumor activities in multiple preclinical murine models. However, no systematic pan-cancer analysis has been conducted to explore PARP11 function. In this study we used multiple databases to assess PARP11 expression, which associations with clinical outcomes, immune checkpoint factors, prognostic significance, genomic characteristics, and immunological aspects. The analysis revealed varying expression levels of PARP11 across different cancer types and a significant correlation between its expression and immune cell infiltration. Insights from the CellMiner database suggest a strong link between PARP11 expression and sensitivity to anticancer drugs, highlighting its potential as a therapeutic target. Moreover, PARP11 expression correlates with patient survival during anti-PD1 and anti-CTLA4 treatments, suggested that PARP11 would be a predictor of immune checkpoint inhibitor (ICI) treatment. In summary, PARP11 would be a potential immunoregulatory target and a diagnosis and prognosis marker for certain types of cancers. The detailed mechanisms of PARP11 in tumor immune responses need to be further investigated.

Spatiotemporal orchestration of macrophage activation trajectories by Vγ4 T cells during skin wound healing.

Dysregulated macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes underlies impaired cutaneous wound healing. This study reveals Vγ4+ γδ T cells spatiotemporally calibrate macrophage trajectories during skin repair via sophisticated interferon-γ (IFN-γ) conditioning across multiple interconnected tissues. Locally within wound beds, infiltrating Vγ4+ γδ T cells directly potentiate M1 activation and suppress M2 polarization thereby prolonging local inflammation. In draining lymph nodes, infiltrated Vγ4+ γδ T cells expand populations of IFN-γ-competent lymphocytes which disseminate systemically and infiltrate into wound tissues, further enforcing M1 macrophages programming. Moreover, Vγ4+γδ T cells flushed into bone marrow stimulate increased IFN-γ production, which elevates the output of pro-inflammatory Ly6C+monocytes. Mobilization of these monocytes continually replenishes the M1 macrophage pool in wounds, preventing phenotypic conversion to M2 activation. Thus, multi-axis coordination of macrophage activation trajectories by trafficking Vγ4+ γδ T cells provides a sophisticated immunological mechanism regulating inflammation timing and resolution during skin repair.

Comprehensive Analysis of Immune Signatures in Primary Biliary Cholangitis and Autoimmune Hepatitis.

Primary Biliary Cholangitis (PBC) and Autoimmune Hepatitis (AIH) are autoimmune diseases that target hepatocytes and bile duct cells, respectively. Despite their shared autoimmune nature, the differences in immunologic characteristics between them remain largely unexplored. This study seeks to elucidate the unique immunological profiles of PBC and AIH, and to identify key differences. We comprehensively analyzed various T-cell subsets and their receptor expression in a cohort of 45 patients, including 27 PBC and 18 AIH cases. Both diseases exhibited T cell exhaustion and senescence along with a surge in inflammatory cytokines. Significantly increased CD38+HLA-DR+CD8+T cell populations were observed in both diseases. AIH was characterized by an upregulation of CD8+TEMRA, CD4+TEM, and CD4+TEMRA cells, and a concurrent reduction in Treg cells. In contrast, PBC displayed a pronounced presence of Tfh cells and a contraction of CD4-CD8-T cell populations. Correlation analysis revealed that NKP46+NK frequency was closely tied to ALT and AST levels, and TIGIT expression on T cells was associated with GLB level in AIH. In PBC, there is a significant correlation between Tfh cells and ALP levels. Moreover, the identified immune landscapes in both diseases strongly related to disease severity. Through logistic regression analysis, γδ T, TIGIT+Vδ2 T, and Tfh1 cell frequencies emerged as distinct markers capable of differentiating PBC from AIH. In conclusion, our analyses reveal that PBC and AIH share similarities and differences regarding to immune profiles. And γδ T, TIGIT+Vδ2 T, and Tfh1 cell frequencies are potential noninvasive immunological markers that can differentiate PBC from AIH.

Therapeutic effects of a novel tylophorine analog, NK-007, on collagen-induced arthritis through suppressing tumor necrosis factor α production and Th17 cell differentiation.

OBJECTIVE: To analyze the effects of a novel compound, NK-007, on the prevention and treatment of collagen-induced arthritis (CIA) and the underlying mechanisms. METHODS: We determined the effect of NK-007 on lipopolysaccharide (LPS)-triggered tumor necrosis factor α (TNFα) production by murine splenocytes and a macrophage cell line (RAW 264.7) by enzyme-linked immunosorbent assay, intracellular cytokine staining, and Western blotting. The LPS-boosted CIA model was adopted, and NK-007 or vehicle was administered at different time points after immunization. Mice were monitored for clinical severity of arthritis, and joint tissues were used for histologic examination, cytokine detection, and immunohistochemical staining. Finally, stability of TNFα production and Th17 cell differentiation were studied using quantitative polymerase chain reaction and flow cytometry. RESULTS: NK-007 significantly suppressed LPS-induced TNFα production in vitro. Administration of NK-007 completely blocked CIA development and delayed its progression. Furthermore, treatment with NK-007 at the onset of arthritis significantly inhibited the progress of joint inflammation. Administration of NK-007 also suppressed production of TNFα, interleukin-6 (IL-6), and IL-17A in the joint and reduced percentages of IL-17+ cells among CD4+ and γ/δ T cells in draining lymph nodes. We further demonstrated that NK-007 acted on the stability of TNFα messenger RNA and reduced Th17 cell differentiation. In addition, it significantly inhibited levels of IL-6 and IL-17A in human coculture assay. CONCLUSION: For its effects on the development and progression of CIA and for its therapeutic effect on CIA, NK-007 has great potential to be a therapeutic agent for human rheumatoid arthritis.

Regulatory role of Vγ1 γδ T cells in tumor immunity through IL-4 production.

It has been demonstrated that the two main subsets of peripheral γδ T cells, Vγ1 and Vγ4, have divergent functions in many diseases models. Recently, we reported that Vγ4 γδ T cells played a protective role in tumor immunity through eomesodermin-controlled mechanisms. However, the precise roles of Vγ1 γδ T cells in tumor immunity, especially whether Vγ1 γδ T cells have any interaction with Vγ4 γδ T cells, remain unknown. We demonstrated in this paper that Vγ1 γδ T cells suppressed Vγ4 γδ T cell-mediated antitumor function both in vitro and in vivo, and this suppression was cell contact independent. Using neutralizing anti-IL-4 Ab or IL-4(-/-) mice, we determined the suppressive factor derived from Vγ1 γδ T cells was IL-4. Indeed, treatment of Vγ4 γδ T cells with rIL-4 significantly reduced expression levels of NKG2D, perforin, and IFN-γ. Finally, Vγ1 γδ T cells produced more IL-4 and expressed significantly higher level of GATA-3 upon Th2 priming in comparison with Vγ4 γδ T cells. Therefore, to our knowledge, our results established for the first time a negative regulatory role of Vγ1 γδ T cells in Vγ4 γδ T cell-mediated antitumor immunity through cell contact-independent and IL-4-mediated mechanisms. Selective depletion of this suppressive subset of γδ T cells may be beneficial for tumor immune therapy.

Vγ4 γδ T cell-derived IL-17A negatively regulates NKT cell function in Con A-induced fulminant hepatitis.

Con A-induced fulminant hepatitis is a well-known animal model for acute liver failure. However, the role of γδ T cells in this model is undefined. In this report, using TCR δ(-/-) mice, we demonstrated a protective role of γδ T cells in Con A-induced hepatitis model. TCR δ(-/-) mice showed significantly decreased levels of IL-17A and IL-17F in the Con A-treated liver tissue, and reconstitution of TCR δ(-/-) mice with wild-type (Wt), but not IL-17A(-/-), γδ T cells significantly reduced hepatitis, strongly suggesting a critical role of IL-17A in mediating the protective effect of γδ T cells. Interestingly, only Vγ4, but not Vγ1, γδ T cells exerted such a protective effect. Furthermore, depletion of NKT cells in TCR δ(-/-) mice completely abolished hepatitis, and NKT cells from Con A-challenged liver tissues of TCR δ(-/-) mice expressed significantly higher amounts of proinflammatory cytokine IFN-γ than those from Wt mice, indicating that γδ T cells protected hepatitis through targeting NKT cells. Finally, abnormal capacity of IFN-γ production by NKT cells of TCR δ(-/-) mice could only be downregulated by transferring Wt, but not IL-17(-/-), Vγ4 γδ T cells, confirming an essential role of Vγ4-derived IL-17A in regulating the function of NKT cells. In summary, our report thus demonstrated a novel function of Vγ4 γδ T cells in mediating a protective effect against Con A-induced fulminant hepatitis through negatively regulating function of NKT cells in an IL-17A-dependent manner, and transferring Vγ4 γδ T cells may provide a novel therapeutic approach for this devastating liver disease.

Expression and prognostic value of DNA sensors in hepatocellular carcinoma.

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.

Mini-review: the distinct roles of STING signaling in tumor immunity-recent progress.

New strategies targeting STING proteins appear promising for eliciting immunotherapeutic responses. Activation of the STING pathway under the right circumstances can drive dendritic cell maturation, antitumor macrophage differentiation, T-cell initiation and activation, natural killer cell activation, vascular reprogramming, and/or cancer cell death, leading to immune-mediated tumor elimination and generation of antitumor immune memory. However, activation of the STING signaling pathway is complicated in tumor immunity. On one hand, STING signaling was found to promote tumor growth. On the other hand, the cGAS-STING pathway has great potential for regulating antitumor immunity. The development of activators of the cGAS-STING pathway may profoundly change tumor immunotherapy, providing an excellent direction for the development and clinical application of immunotherapeutic strategies for related diseases. This review provides a concise summary of the role of the STING pathway in tumors in recent years.

Multi-omics analysis of TLCD1 as a promising biomarker in pan-cancer.

Background: The TLC Domain Containing 1 (TLCD1) protein, a key regulator of phosphatidylethanolamine (PE) composition, is distributed across several cellular membranes, including mitochondrial plasma membranes. Existing research has revealed the impact of TLCD1 on the development of non-alcoholic fatty liver disease. However, there remains a gap in comprehensive pan-cancer analyses of TLCD1, and the precise role of TLCD1 in cancer patient prognosis and immunological responses remains elusive. This study aims to provide a comprehensive visualization of the prognostic landscape associated with TLCD1 across a spectrum of cancers, while shedding light on the potential links between TLCD1 expression within the tumor microenvironment and immune infiltration characteristics. Methods: TLCD1 expression data were obtained from GTEx, TCGA, and HPA data repositories. Multiple databases including TIMER, HPA, TISIDB, cBioPortal, GEPIA2, STRING, KEGG, GO, and CancerSEA were used to investigate the expression pattern, diagnostic and prognostic significance, mutation status, functional analysis, and functional status of TLCD1. In addition, we evaluated the relationship between TLCD1 expression and immune infiltration, tumor mutational burden (TMB), microsatellite instability (MSI), and immune-related genes in pan-cancer. Furthermore, the association of TLCD1 with drug sensitivity was analyzed using the CellMiner database. Results: We found that TLCD1 is generally highly expressed in pan-cancers and is significantly associated with the staging and prognosis of various cancers. Furthermore, our results also showed that TLCD1 was significantly associated with immune cell infiltration and immune regulatory factor expression. Using CellMiner database analysis, we then found a strong correlation between TLCD1 expression and sensitivity to anticancer drugs, indicating its potential as a therapeutic target. The most exciting finding is that high TLCD1 expression is associated with worse survival and prognosis in GBM and SKCM patients receiving anti-PD1 therapy. These findings highlight the potential of TLCD1 as a predictive biomarker for response to immunotherapy. Conclusion: TLCD1 plays a role in the regulation of immune infiltration and affects the prognosis of patients with various cancers. It serves as both a prognostic and immunologic biomarker in human cancer.

Naturally activated V gamma 4 gamma delta T cells play a protective role in tumor immunity through expression of eomesodermin.

We previously demonstrated that gammadelta T cells played an important role in tumor immune surveillance by providing an early source of IFN-gamma. The precise role of different subsets of gammadelta T cells in the antitumor immune response, however, is unknown. Vgamma1 and Vgamma4 gammadelta T cells are the principal subsets of peripheral lymphoid gammadelta T cells and they might play distinct roles in tumor immunity. In support of this, we observed that reconstitution of TCRdelta(-/-) mice with Vgamma4, but not Vgamma1, gammadelta T cells restored the antitumor response. We also found that these effects were exerted by the activated (CD44(high)) portion of Vgamma4 gammadelta T cells. We further determined that IFN-gamma and perforin are critical elements in the Vgamma4-mediated antitumor immune response. Indeed, CD44(high) Vgamma4 gammadelta T cells produced significantly more IFN-gamma and perforin on activation, and showed greater cytolytic activity than did CD44(high) Vgamma1 gammadelta T cells, apparently due to the high level of eomesodermin (Eomes) in these activated Vgamma4 gammadelta T cells. Consistently, transfection of dominant-negative Eomes in Vgamma4 gammadelta T cells diminished the level of IFN-gamma secretion, indicating a critical role of Eomes in the effector function of these gammadelta T cells. Our results thus reveal distinct functions of Vgamma4 and Vgamma1 gammadelta T cells in antitumor immune response, and identify a protective role of activated Vgamma4 gammadelta T cells, with possible implications for tumor immune therapy.

Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance.

Hepatocellular carcinoma (HCC) is highly malignant and prone to metastasize due to the heterogeneous and immunosuppressive tumor microenvironment (TME). Programmed cell deaths (PCDs) including apoptosis, ferroptosis, and pyroptosis routinely occur in the HCC TME and participate in tumorigenesis. However, how apoptosis, ferroptosis, and pyroptosis are involved in constructions of the immunosuppressive TME and their underlying cross-talk remains to be further unveiled. In this work, we deciphered the immunosuppressive landscape of HCC TME, which demonstrated high expressions of inhibitory checkpoint molecules and infiltration of protumor immune cells but low infiltration of antitumor effector immune cells. Further investigations unequivocally revealed that marker genes of apoptosis, ferroptosis, and pyroptosis are closely correlated with expressions and infiltrations of inhibitory checkpoint molecules and immune cells and that higher "-optosis" links to poorer patient prognosis. Notably, such three types of "-optosis" interact with each other at both the gene and protein levels, suggesting that they conspiringly induce the establishment of the immunosuppressive HCC TME. Interestingly, examinations of circulating γδ T cells in HCC patients revealed a noticeable dysfunction phenotype. The strikingly elevated ratio of the Vδ1+ versus the Vδ2+ subset suggested that the Vδ1+/Vδ2+ ratio would be a potential biomarker for the diagnosis and prognosis in HCC patients. Altogether, this work thoroughly decrypted the underlying correlations between apoptosis, ferroptosis, and pyroptosis and the formation of immunosuppressive HCC TME and, meanwhile, indicated that allogeneic Vδ2+ γδ T-cell transfer would be a promising adjuvant strategy for renormalizing circulating γδ T cell and thus achieving sound clinical efficacy against HCC.

TBK1-METTL3 axis facilitates antiviral immunity.

mRNA m6A modification is heavily involved in modulation of immune responses. However, its function in antiviral immunity is controversial, and how immune responses regulate m6A modification remains elusive. We here find TBK1, a key kinase of antiviral pathways, phosphorylates the core m6A methyltransferase METTL3 at serine 67. The phosphorylated METTL3 interacts with the translational complex, which is required for enhancing protein translation, thus facilitating antiviral responses. TBK1 also promotes METTL3 activation and m6A modification to stabilize IRF3 mRNA. Type I interferon (IFN) induction is severely impaired in METTL3-deficient cells. Mettl3fl/fl-lyz2-Cre mice are more susceptible to influenza A virus (IAV)-induced lethality than control mice. Consistently, Ythdf1-/- mice show higher mortality than wild-type mice due to decreased IRF3 expression and subsequently attenuated IFN production. Together, we demonstrate that innate signals activate METTL3 via TBK1, and METTL3-mediated m6A modification secures antiviral immunity by promoting mRNA stability and protein translation.

IL-1ß-activated mTORC2 promotes accumulation of IFN-γ+ γδ T cells by upregulating CXCR3 to restrict hepatic fibrosis.

Liver fibrosis represents a severe stage of liver damage, with hallmarks of inflammation, hepatic stellate cell activation, and extracellular matrix accumulation. Although previous studies demonstrated γδ T cells are involved in liver fibrosis, the precise role and mechanisms of γδ T cells migrating to fibrotic liver have not been elucidated. Here, we aim to investigate the functional subsets of γδ T cells in hepatic fibrosis and to further explore the underlying causes and drivers of migration. In this study, we observed that γδ T cells accumulate in fibrotic liver. Adoptive transfer of γδ T, especially Vγ4 γδ T subset, can significantly alleviate liver fibrosis. In addition, CCl4 treatment also leads to activation of mTOR signaling in γδ T cells. Genetic deletion of the Rictor gene, but not Raptor, in γδ T cells markedly exacerbated liver fibrosis. Mechanistically, CCl4-induced liver injury causes macrophage accumulation in the liver, and IL-1ß produced by macrophages promotes mTORC2 signaling activation in γδ T cells, which upregulates T-bet expression and eventually promotes CXCR3 transcription to drive γδ T cell migration. Moreover, hepatic γδ T cells ameliorated liver fibrosis by cytotoxicity against activated hepatic stellate cells in FasL-dependent manner, and secrete IFN-γ to inhibit the differentiation of pro-fibrotic Th17 cells. Thus, IL-1ß-activated mTORC2 signaling in γδ T cells upregulates CXCR3 expression, which is critical for IFN-γ+ γδ T cells migration into the liver and amelioration of liver fibrosis. Our findings indicate that targeting the mTORC2 or CXCR3 in γδ T cells could be considered as a promising approach for γδ T cell immunotherapy against liver fibrosis.