Protein tyrosine phosphatase non-receptor Ⅱ:A possible biomarker of poor prognosis and mediator of immune evasion in hepatocellular carcinoma

BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of cases.HCC is the most common primary liver cancer.China has the highest incidence and mortality rate of HCC in the world,and it is one of the malignant tumors that seriously threaten the health of Chinese people.The onset of liver cancer is occult,the early cases lack typical clinical symptoms,and most of the patients are already in the middle and late stage when diagnosed.Therefore,it is very important to find new markers for the early detection and diagnosis of liver cancer,improve the therapeutic effect,and improve the prognosis of patients.Protein tyrosine phosphatase non-receptor 2(PTPN2)has been shown to be associated with colorectal cancer,triple-negative breast cancer,non-small cell lung cancer,and prostate cancer,but its biological role and function in tumors remain to be further studied.AIM To combine the results of relevant data obtained from The Cancer Genome Atlas(TCGA)to provide the first in-depth analysis of the biological role of PTPN2 in HCC.METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database,and the findings were then verified by immunohistochemical staining,quantitative real-time polymerase chain reaction(qRT-PCR),and immunoblotting.The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features.Finally,the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining.RESULTS The results of immunohistochemical staining,qRT-PCR,and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways,including cancer-related pathways,the Notch signaling pathway,and the MAPK signaling pathway.Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways,such as the epithelial mesenchymal transition process.A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group.CONCLUSION This study investigated PTPN2 from multiple biological perspectives,revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.

Plexin domain-containing 1 may be a biomarker of poor prognosis in hepatocellular carcinoma patients,may mediate immune evasion

BACKGROUND For the first time,we investigated the oncological role of plexin domain-containing 1(PLXDC1),also known as tumor endothelial marker 7(TEM7),in hepatocellular carcinoma(HCC).AIM To investigate the oncological profile of PLXDC1 in HCC.METHODS Based on The Cancer Genome Atlas database,we analyzed the expression of PLXDC1 in HCC.Using immunohistochemistry,quantitative real-time polymerase chain reaction(qRT-PCR),and Western blotting,we validated our results.The prognostic value of PLXDC1 in HCC was analyzed by assessing its correlation with clinicopathological features,such as patient survival,methylation level,tumor immune microenvironment features,and immune cell surface checkpoint expression.Finally,to assess the immune evasion potential of PLXDC1 in HCC,we used the tumor immune dysfunction and exclusion(TIDE)website and immunohistochemical staining assays.RESULTS Based on immunohistochemistry,qRT-PCR,and Western blot assays,overexpression of PLXDC1 in HCC was associated with poor prognosis.Univariate and multivariate Cox analyses indicated that PLXDC1 might be an independent prognostic factor.In HCC patients with high methylation levels,the prognosis was worse than in patients with low methylation levels.Pathway enrichment analysis of HCC tissues indicated that genes upregulated in the high-PLXDC1 subgroup were enriched in mesenchymal and immune activation signaling,and TIDE assessment showed that the risk of immune evasion was significantly higher in the high-PLXDC1 subgroup compared to the low-PLXDC1 subgroup.The high-risk group had a significantly lower immune evasion rate as well as a poor prognosis,and PLXDC1-related risk scores were also associated with a poor prognosis.CONCLUSION As a result of this study analyzing PLXDC1 from multiple biological perspectives,it was revealed that it is a biomarker of poor prognosis for HCC patients,and that it plays a role in determining immune evasion status.

Accurate Diagnosis of SARS-CoV-2 JN.1 by Sanger Sequencing of Receptor-Binding Domain Is Needed for Clinical Evaluation of Its Immune Evasion

Background: Omicron JN.1 has become the dominant SARS-CoV-2 variant in recent months. JN.1 has the highest number of amino acid mutations in its receptor binding domain (RBD) and has acquired a hallmark L455S mutation. The immune evasion capability of JN.1 is a subject of scientific investigation. The US CDC used SGTF of TaqPath COVID-19 Combo Kit RT-qPCR as proxy indicator of JN.1 infections for evaluation of the effectiveness of updated monovalent XBB.1.5 COVID-19 vaccines against JN.1 and recommended that all persons aged ≥ 6 months should receive an updated COVID-19 vaccine dose. Objective: Recommend Sanger sequencing instead of proxy indicator to diagnose JN.1 infections to generate the data based on which guidelines are made to direct vaccination policies. Methods: The RNA in nasopharyngeal swab specimens from patients with clinical respiratory infection was subjected to nested RT-PCR, targeting a 398-base segment of the N-gene and a 445-base segment of the RBD of SARS-CoV-2 for amplification. The nested PCR amplicons were sequenced. The DNA sequences were analyzed for amino acid mutations. Results: The N-gene sequence showed R203K, G204R and Q229K, the 3 mutations associated with Omicron BA.2.86 (+JN.1). The RBD sequence showed 24 of the 26 known amino acid mutations, including the hallmark L455S mutation for JN.1 and the V483del for BA.2.86 lineage. Conclusions: Sanger sequencing of a 445-base segment of the SARS-CoV-2 RBD is useful for accurate determination of emerging variants. The CDC may consider using Sanger sequencing of the RBD to diagnose JN.1 infections for statistical analysis in making vaccination policies.

Immune evasion and therapeutic opportunities based on natural killer cells

Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy.Although several studies have shown the promising antitumor effects of NK cells in immunotherapy,their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death.Thus,for efficient tumor immunotherapy,the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood.Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered.In this review,we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression[NKG2A,programmed cell death1(PD-1),and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif(TIGIT)]on the NK cell surface,and thus inhibit NK cell activity.We also reviewed the current status of treatments based on these surface molecules.By comparing the therapeutic effects related to the treatment status and bypass mechanisms,we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.

Immune evasion mechanisms and therapeutic strategies in gastric cancer

Gastric cancer(GC)is a malignancy with a high incidence and mortality.The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression.Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion.In this review,we systematically summarize the intricate crosstalk between GC cells and immune cells,including tumor-associated macrophages,neutrophils,myeloid-derived suppressor cells,natural killer cells,effector T cells,regulatory T cells,and B cells.We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack.We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies,both alone and in combination with conventional therapies.Anti-cytotoxic Tlymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment.However,the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients.This review provides a comprehensive understanding of the immune evasion mechanisms of GC,and highlights promising immunotherapeutic strategies.

EXPRESSION OF FLIP IN HUMAN COLON CARCINOMAS: A NEW MECHANISM OF IMMUNE EVASION

Objective： It has been proposed that Fas ligand （FasL） may play an important role in immune escape of tumors and FLIP is an important mediator of Fas/FasL pathway. In this study, the expression of FLIP was determined in human colon carcinoma cell lines and tissue to investigate the new mechanism of immune evasion of human colon carcinomas. Methods： RT-PCR and immunohistochemistry （IHC） were performed to investigate the expression of FLIP in human colon carcinoma cell lines SW480, LS174 and twenty human primary colon carcinoma specimens. Results： It was shown that SW480 cells, LS174 cells and primary colon carcinoma specimen constitutively expressed FLIP at the mRNA and protein level. The expression of FLIP was not found in the epithelial cells of normal colon mucosa. Conclusion： FLIP was expressed in human primary colon carcinoma specimens but not in the normal counterpart. It suggested that the expression of FLIP may occur during the malignant transformation from normal colon epithelial cells to colon carcinoma cells. Tumor cells might obtain the ability to resist the Fas-mediated apoptosis by expressing FLIP. The expression of FLIP might contribute to the formation of colon carcinomas.

Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases

The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses,thus allowing continuous tumor growth and development.Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer.Compared with other cancers,pancreatic cancer has a tumor microenvironment that can resist most treatment modalities,including emerging immunotherapy.Sadly,the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients,suggesting that pancreatic cancer has successfully evaded immunomodulation.In this review,we summarize the impact of genetic alteration and epigenetic modification(especially histone deacetylases,HDAC)on immune evasion in pancreatic cancer.HDAC overexpression significantly suppresses tumor suppressor genes,contributing to tumor growth and progression.We review the evidence on HDAC inhibitors in tumor eradication,improving T cells activation,restoring tumor immunogenicity,and modulating programmed death 1 interaction.We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.

The effects of IL-10 on acute leukemic immune evasion

Objective: To explore the effects of IL-10 on acute leukemic immune evasion.Methods: Plasma concentrations of IL-10 were measured by ELISA in 56 first-visit acute leukemic patients.And expressions of IL-10 on leukemic cells in 30 patients were measured by indirect immunofluorescence technique. Results:Compared with those in control group,IL-10 concentrations increased significantly in first-visit acute leukemic patients.And there was a slight but not significant decrease of IL-10 in patients with acute lymphocytic leukemia(ALL) compared with those with acute non lymphocytic leukemic(ANLL).After intensive chemotherapy,there was a significant decrease of IL-10 in completely remitted(CR) patients,especially in those with ANLL,but there was still a significant increase compared with those in control group.The positive rate of cells giving out yellow-green bright fluorescence on membranes was 10%-80%;there were 18 patients expressing IL-10(18/30,60%) positively:among them 11 with ANLL(11/19,58%) and 7 with ALL(7/11,64%) respectively while that of peripheral mononucleate cells in control group was 13%.Compared with that in control group,there was a significant increase of positive rate in ANLL and ALL but with no significant difference between ANLL and ALL.Conclusion: Probably as one of important mechanisms of acute leukemic immune evasion,IL-10 secreted by leukemic cells,contributing to the immunosuppressive state at the tumor site,increase significantly in acute leukemic patients.

Research Hotspot and Application Status of Immune Evasion Mechanism in Ovarian Cancer

Ovarian cancer is one of the three major malignant tumors in gynecology, with increasing incidence and mortality rates. Currently, the main treatment methods remain surgical intervention in combination with chemotherapy. However, due to its high recurrence rate and the risk of drug resistance, the overall prognosis is poor. Ovarian cancer has been identified as an immunegenic tumor, and in recent years, with the continued advancement of research into immune evasion mechanisms, immunotherapy has emerged as a groundbreaking treatment modality. This article will focus on the immune escape mechanisms and their application in ovarian cancer, providing a comprehensive overview of its current status and the challenges it faces.

Immune evasion by Plasmodium falciparum parasites: converting a host protection mechanism for the parasite′s benefit

Immune evasion is a strategy used by pathogenic microbes to evade the host immune system in order to ensure successful propagation. Immune evasion is particularly important for the blood stages of Plasmodium falciparum, the causative agent of the deadly disease malaria tropica. Because Plasmodium blood stage parasites require human erythrocytes for replication, their ability to evade attack by the human immune system is essential for parasite survival. In order to escape immunity-induced killing, the intraerythrocytic parasites have evolved a variety of evasion mechanisms, including expansion of plasmodial surface proteins, organ-specific sequestration of the infected red blood cells and acquisition of immune-regulatory proteins by the parasite. This review aims to highlight recent advances in the molecular understanding of the immune evasion strategies by P. falciparum, including antigenic variation, surface protein polymorphisms and invasion ligand diversification. The review will further discuss new findings on the regulatory mechanisms applied by P. falciparum to avoid lysis by the human complement as well as killing by immune factors of the mosquito vector.

Loss-of-function mutations of microRNA-142-3p promote ASH1L expression to induce immune evasion and hepatocellular carcinoma progression

BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.

PKCαinhibitors promote breast cancer immune evasion by maintaining PD-L1 stability

Protein kinase Cα(PKCα)regulates diverse biological functions of cancer cells and is a promising therapeutic target.However,clinical trials of PKC-targeted therapies have not yielded satisfactory results.Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms.In this study,we found that PKCαinhibition enhances CD8+T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice.We further identified PKCαas a critical regulator of programmed cell death-ligand 1(PD-L1)and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression.We demonstrated that PKCα-mediated PD-L1 phosphorylation promotes PD-L1 degradation throughβtransducin repeat-containing protein.Notably,the efficacy of PKCαinhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo.Clinical analysis revealed that PKCαexpression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer.This study demonstrated the antitumor capability of PKCα,identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies,and provided a proof of concept for targeting PKCαin combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer,especially TNBC.

The unique immune evasion mechanisms of the mpox virus and their implication for developing new vaccines and immunotherapies

Mpox is an infectious and contagious zoonotic disease caused by the mpox virus(MPXV),which belongs to the genus Orthopoxvirus.Since 2022,MPXV has posed a significant threat to global public health.The emergence of thousands of cases across the Western Hemisphere prompted the World Health Organization to declare an emergency.The extensive coevolutionary history of poxviruses with humans has enabled these viruses to develop sophisticated mechanisms to counter the human immune system.Specifically,MPXV employs unique immune evasion strategies against a wide range of immunological elements,presenting a considerable challenge for treatment,especially following the discontinuation of routine smallpox vaccination among the general population.In this review,we start by discussing the entry of the mpox virus and the onset of early infection,followed by an introduction to the mechanisms by which the mpox virus can evade the innate and adaptive immune responses.Two caspase-1 inhibitory proteins and a PKR escape-related protein have been identified as phylogenomic hubs involved in modulating the immune environment during the MPXV infection.With respect to adaptive immunity,mpox viruses exhibit unique and exceptional T-cell inhibition capabilities,thereby comprehensively remodeling the host immune environment.The viral envelope also poses challenges for the neutralizing effects of antibodies and the complement system.The unique immune evasion mechanisms employed by MPXV make novel multi-epitope and nucleic acid-based vaccines highly promising research directions worth investigating.Finally,we briefly discuss the impact of MPXV infection on immunosuppressed patients and the current status of MPXV vaccine development.This review may provide valuable information for the development of new immunological treatments for mpox.

Local TSH/TSHR signaling promotes CD8^(+) T cell exhaustion and immune evasion in colorectal carcinoma

Dysfunction of CD8^(+)T cells in the tumor microenvironment(TME)contributes to tumor immune escape and immunotherapy tolerance.The effects of hormones such as leptin,steroid hormones,and glucocorticoids on T cell function have been reported previously.However,the mechanism underlying thyroid-stimulating hormone(TSH)/thyroid-stimulating hormone receptor(TSHR)signaling in CD8^(+)T cell exhaustion and tumor immune evasion remain poorly understood.This study was aimed at investigating the effects of TSH/TSHR signaling on the function of CD8^(+)T cells and immune evasion in colorectal cancer(CRC).Methods:TSHR expression levels in CD8^(+)T cells were assessed with immunofluorescence and flow cytometry.Functional investigations involved manipulation of TSHR expression in cellular and mouse models to study its role in CD8^(+)T cells.Mechanistic insights were mainly gained through RNAsequencing,Western blotting,chromatin immunoprecipitation and luciferase activity assay.Immunofluorescence,flow cytometry and Western blotting were used to investigate the source of TSH and TSHR in CRC tissues.Results:TSHR was highly expressed in cancer cells and CD8^(+)T cells in CRC tissues.TSH/TSHR signaling was identified as the intrinsic pathway promoting CD8^(+)T cell exhaustion.Conditional deletion of TSHR in CD8^(+)tumorinfiltrating lymphocytes(TILs)improved effector differentiation and suppressed the expression of immune checkpoint receptors such as programmed cell death 1(PD-1)and hepatitis A virus cellular receptor 2(HAVCR2 or TIM3)through the protein kinase A(PKA)/cAMP-response element binding protein(CREB)signaling pathway.CRC cells secreted TSHR via exosomes to increase the TSHR level in CD8^(+)T cells,resulting in immunosuppression in the TME.Myeloid-derived suppressor cells(MDSCs)was the main source of TSH within the TME.Low expression of TSHR in CRC was a predictor of immunotherapy response.Conclusions:The present findings highlighted the role of endogenous TSH/TSHR signaling in CD8^(+)T cell exhaustion and immune evasion in CRC.TSHR may be suitable as a predictive and therapeutic biomarker in CRC immunotherapy.

Tracking interactions between TAMs and CAFs mediated by arginase-induced proline production during immune evasion of HCC

Synergistic changes between tumor-associated macrophages(TAMs)and cancer-associatedfibroblasts(CAFs)aggravated immune evasion of hepatocellular carci-noma(HCC),however,the underlying molecular mechanisms remain elusive.Their continuous and dynamic interactions are subject to bioactive molecule changes.A real-time and in situ monitoring method suitable for in vivo research of these processes would be indispensable but is scarce.In this study,a dual imaging strat-egy that tracing the TAMs and CAFs simultaneously was developed using a new arginase-specific probe and established CAFs-specific probe.The emerging roles of arginase in mediating CAFs activation in mice were explored.Results showed arginase up-regulation in TAMs,followed by proline increase.Subsequently,proline produced by TAMs initiated the activation of CAFs.Through the JAK-STAT sig-naling,CAFs up-regulated the PD-L1 and CTLA-4,ultimately promoting immune evasion of HCC.This study revealed a new mechanism by which TAMs and CAFs collaborate in immune evasion,providing new targets for HCC immunotherapy.

Emerging role of metabolic reprogramming in tumor immune evasion and immunotherapy

Mounting evidence has revealed that the therapeutic efficacy of immunotherapies is restricted to a small portion of cancer patients.A deeper understanding of how metabolic reprogramming in the tumor microenvironment(TME)regulates immunity remains a major challenge to tumor eradication.It has been suggested that metabolic reprogramming in the TME may affect metabolism in immune cells and subsequently suppress immune function.Tumor cells compete with infiltrating immune cells for nutrients and metabolites.Notably,the immunosuppressive TME is characterized by catabolic and anabolic processes that are critical for immune cell function,and elevated inhibitory signals may favor cancer immune evasion.The major energy sources that supply different immune cell subtypes also undergo reprogramming.We herein summarize the metabolic remodeling in tumor cells and different immune cell subtypes and the latest advances underlying the use of metabolic checkpoints in antitumor immunotherapies.In this context,targeting both tumor and immune cell metabolic reprogramming may enhance therapeutic efficacy.

Cytomegalovirus immune evasion by perturbation ot endosomal trafficking

Cytomegaloviruses （CMVs）, members of the herpesvirus family, have evolved a variety of mechanisms to evade the immune response to survive in infected hosts and to establish latent infection, They effectively hide infected cells from the effector mechanisms of adaptive immunity by eliminating cellular proteins （major histocompatibility Class I and Class II molecules） from the cell surface that display viral antigens to CD8 and CD4 T lymphocytes, CMVs also successfully escape recognition and elimination of infected cells by natural killer （NK） cells, effector cells of innate immunity, either by mimicking NK cell inhibitory ligands or by downregulating NK cell-activating ligands, To accomplish these immunoevasion functions, CMVs encode several proteins that function in the biosynthetic pathway by inhibiting the assembly and trafficking of cellular proteins that participate in immune recognition and thereby, block their appearance at the cell surface, However, elimination of these proteins from the cell surface can also be achieved by perturbation of their endosomal route and subsequent relocation from the cell surface into intracellular compartments, Namely, the physiological route of every cellular protein, including immune recognition molecules, is characterized by specific features that determine its residence time at the cell surface, In this review, we summarize the current understanding of endocytic trafficking of immune recognition molecules and perturbations of the endosomal system during infection with CMVs and other members of the herpesvirus family that contribute to their immune evasion mechanisms,

Elevated nuclear PIGL disrupts the cMyc/BRD4 axis and improves PD-1 blockade therapy by dampening tumor immune evasion

To improve the efficacy of lenvatinib in combination with programmed death-1(PD-1)blockade therapy for hepatocellular carcinoma(HCC),we screened the suppressive metabolic enzymes that sensitize HCC to lenvatinib and PD-1 blockade,thus impeding HCC progression.After analysis of the CRISPR‒Cas9 screen,phosphatidylinositol-glycan biosynthesis class L(PIGL)ranked first in the positive selection list.PIGL depletion had no effect on tumor cell growth in vitro but reprogrammed the tumor microenvironment(TME)in vivo to support tumor cell survival.Specifically,nuclear PIGL disrupted the interaction between cMyc/BRD4 on the distant promoter of target genes and thus decreased the expression of CCL2 and CCL20,which are involved in shaping the immunosuppressive TME by recruiting macrophages and regulatory T cells.PIGL phosphorylation at Y81 by FGFR2 abolished the interaction of PIGL with importinα/β1,thus retaining PIGL in the cytosol and facilitating tumor evasion by releasing CCL2 and CCL20.Clinically,elevated nuclear PIGL predicts a better prognosis for HCC patients and presents a positive correlation with CD8+T-cell enrichment in tumors.Clinically,our findings highlight that the nuclear PIGL intensity or the change in PIGL-Y81 phosphorylation should be used as a biomarker to guide lenvatinib with PD-1 blockade therapy.

An update: Epstein-Barr virus and immune evasion via microRNA regulation

Epstein-Barr virus(EBV) is an oncogenic virus that ubiquitously establishes life-long persistence in humans. To ensure its survival and maintain its B cell transformation function, EBV has developed powerful strategies to evade host immune responses. Emerging evidence has shown that micro RNAs(mi RNAs) are powerful regulators of the maintenance of cellular homeostasis. In this review, we summarize current progress on how EBV utilizes mi RNAs for immune evasion. EBV encodes mi RNAs targeting both viral and host genes involved in the immune response. The mi RNAs are found in two gene clusters, and recent studies have demonstrated that lack of these clusters increases the CD4^+ and CD8^+ T cell response of infected cells. These reports strongly indicate that EBV mi RNAs are critical for immune evasion. In addition, EBV is able to dysregulate the expression of a variety of host mi RNAs, which influence multiple immune-related molecules and signaling pathways. The transport via exosomes of EBV-regulated mi RNAs and viral proteins contributes to the construction and modification of the inflammatory tumor microenvironment.During EBV immune evasion, viral proteins, immune cells, chemokines, pro-inflammatory cytokines, and pro-apoptosis molecules are involved. Our increasing knowledge of the role of mi RNAs in immune evasion will improve the understanding of EBV persistence and help to develop new treatments for EBV-associated cancers and other diseases.

Germline genomes have a dominant-heritable contribution to cancer immune evasion and immunotherapy response

Background:Immune evasion is a fundamental hallmark for cancer.At the early stages of tumor development,immune evasion strategies must be implemented by tumors to prevent attacks from the host immune systems.Blocking tumors5 immune evasion will re-activate the host immune systems to eliminate tumors.Immune-checkpoint therapy(ICT)which applies anti-PD-l/PD-Ll or anti-CTLA4 treatment has been a remarkable success in the past few years.However,〜70%of patients cannot gain any clinical benefits from ICT treatment due to the tumorimmunity system's complexity・In the past,germline pathogenic variants have been thought to have only minorheritable contributions to cancer.Results:Emerging evidence has shown that germline genomes play a dominant-heritable contribution to cancer via encoding the host immune system.The functional components of the immune system are encoded by the host genome,thus the germline genome might have a profound impact on cancer immune evasion and immunotherapy response.Indeed,recent studies showed that germline pathogenic variants can influence immune capacity in cancer patients at a population level by(i)shaping tumor somatic mutations,altering methylation patterns and antigen-presentation capacity or(ii)influencing NK cell's function to modulate lymphocyte infiltration in the tumor microenvironment.In addition,the HLA(types A,B or C)genotypes also shape the landscape of tumor somatic mutations.Conclusion:These results highlight the indispensable roles of germline genome in immunity and cancer development and suggest that germline genomics should be integrated into the research field of cancer biology and cancer immunotherapy.