Tumor-infiltrating T-Lymphocyte immunity-related immune tolerance and anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy for advanced hepatocellular carcinoma

Systemic therapy has become the standard treatment for patients with advanced hepatocellular carcinoma(HCC)whose treatment options are limited.However,the long-term patient response to drugs and the survival outcomes remain a concern.With increasing exploration of the HCC microenvironment,particularly in terms of T lymphocyte immunity,a new era of immunomolecular targeted therapy,based on molecular signaling,has arrived for advanced HCC.In the study of immune tolerance of the intrinsic HCC microenvironment,we found that multiple immunosuppressive mechanisms and immune checkpoint inhibitors,such as anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy,have improved clinical outcomes in some patients with advanced HCC.Furthermore,various combination therapies have been investigated,and HCC types have been categorized into different types based on anti–programmed cell death protein 1(PD-1)/ligand of programmed cell death protein 1(PD-L1)treatment.In this paper,we first discuss the tumor-infiltrating T lymphocyte immunity and immune tolerance of HCC.We then clarify the basic mechanism of anti–PD-1/PD-L1 therapy and discuss the types of HCC based on anti–PD-1/PD-L1 therapy.Thereafter,we explain the relevant studies and mechanisms of combination therapy of anti–PD-1/PD-L1 with antiangiogenesis drugs or multikinase kinase inhibitors,anti–T lymphocyte–related signaling pathways in HCC,and other anti-CD8+T cell immune checkpoints.In this way,this review offers a deeper understanding of anti–PD-1/PD-L1 immunotherapy for advanced HCC,in order to provide better individualized treatments for patients with advanced HCC.

Research progress of ICOSL/ICOS pathway in maternal-fetal immune tolerance

Co-signaling molecules are molecules whose ligands on the surface of cells interact with receptors on the surface of T cells to convey stimulatory or inhibitory signals to regulate immune responses.Co-signaling molecules play an important role in tumor and autoimmune diseases.Lately,studies have shown that co-signaling molecules are also involved in the regulation of maternal-fetal immune tolerance,and abnormalities of co-signaling molecules may lead to the imbalance of maternal-fetal immune tolerance,resulting in recurrent abortion,eclampsia and other pregnancy complications.ICOSL/ICOS is a ligand and receptor of costimulatory signals,which regulates maternal and fetal immune tolerance by participating in T cell differentiation and Th1 and Th2 cytokine secretion.Therefore,this article reviews the structure of ICOSL/ICOS,the distribution of ICOSL/ICOS at the maternal-fetal interface and its immune regulation during pregnancy,in order to provide new ideas for the future study of immunotherapy of pregnancy complications caused by abnormal co-signaling molecules.

Ragweed pollen induces allergic conjunctivitis immune tolerance in mice via regulation of the NF-κB signal pathway

AIM:To investigate the feasibility and mechanism of immune tolerance in allergic conjunctivitis.METHODS:The allergic conjunctivitis immune tolerance mice model was established by ragweed pollen(RW)and the related cytokines were detected.The mice were divided into 9 groups and the maslinic acid(MA)or PBS were given for different group after modeling.The expression levels of chemokine ligand 5(CCL5)and P-65 in the conjunctival tissue were analyzed by immunohistochemistry,quantitative reverse transcription polymerase chain reaction(q RT-PCR)and Western blot.The percentage of interleukin-17(IL-17)and CD4+CD25+in the splenocyte supernatant was analyzed by flow cytometry.Fur thermore,the serum and splenocyte supernatant concentration of total-IgE,interleukin-10(IL-10),and IL-17 was analyzed by enzyme linked immune response(ELISA).RESULTS:After the model was established,symptoms of conjunctivitis were alleviated,the level of P-65,CCL5,IL-17,and total-IgE was raised,while the expression of IL-10,CD4+CD25+was decreased.This result fully demonstrated that a typical IL-17/regulatory-T-cells(Treg cells)imbalance and NF-κB activation.When the NF-κB signal pathway was suppressed,it showed that there was a further relief of conjunctivitis in mice.At the same time,the expression of total-IgE,IL-17,and CCL5 was decreased and the expression of anti-inflammatory factor(IL-10,CD4+CD25+)was increased.CONCLUSION:In the state of immune tolerance,symptoms of conjunctivitis in mice are alleviated,the Th-17 cells of allergic conjunctivitis mice are inhibited,and Treg cells activity is enhanced.

Diverse Roles of Immune Cells in Transplant Rejection and Immune Tolerance

Organ transplant rejection(OTR)is a complex immune reaction involving multiple cells,and it determines graft survival and patient prognosis.At present,most transplant recipients are administered a combination of immunosuppressive and biological agents to protect them from OTR.However,immunosuppressive agents negatively impact the immune system of the patients,causing them to suffer from serious complications,such as chronic infection and malignant tumors.Therefore,a thorough understanding of the mechanisms involved in immune tolerance and immune rejection with regard to organ transplant(OT)is essential for developing better treatment options and improving patient outcomes.This article reviews the role of immune cells in OTR and organ transplant tolerance(OTT),including the novel cell therapies that are currently under clinical trials for transplant recipients.

IMMUNE TOLERANCE INDUCED BY GAMMA-RAY IRRADIATION

Objective: To detect the existence of immune tolerance induced by gamma-ray irradiation. Methods: Peritoneal cells were harvested from mice subjected to 5 Gy 60Co gamma-ray total body irradiation at 3d, 7d, 15d and 30d, then their counts, morphological changes and IL-12 gene expression were investigated. Results: After irradiation, the peritoneal cells were sharply reduced, the cell morphology shifted from round-like to polymorphic and fusiform with some processes, expression of IL-12 p35 was seriously suppressed, while that of IL-12 p40 greatly enhanced. Conclusion: Our data highly suggest that the gamma-ray irradiation could potentially induce dendritic cell (DC) commitment and immune tolerance.

Sinomenine promotes differentiation of induced pluripotent stem cells into immature dendritic cells with high induction of immune tolerance

BACKGROUND Immature dendritic cells(imDCs)play an important role in the induction of donor-specific transplant immunotolerance.However,these cells have limitations,such as rapid maturation and a short lifespan in vivo.In previous studies,induced pluripotent stem cells(iPSCs)differentiated into imDCs,and sinomenine(SN)was used to inhibit the maturation of imDCs.AIM To study the capacity of SN to maintain iPSC-derived imDCs(SN-iPSCs-imDCs)in an immature state and the mechanism by which SN-iPSCs-imDCs induce immunotolerance.METHODS In this study,mouse iPSCs were induced to differentiate into imDCs in culture medium without or with SN(iPSCs-imDCs and SN-iPSCs-imDCs).The imDCrelated surface markers,endocytotic capacity of fluorescein isothiocyanate Dextran and apoptosis were analyzed by flow cytometry.The effects of iPSCs-imDCs and SNiPSCs-imDCs on T-cell stimulatory function,and regulatory T(Treg)cell proliferative function in vitro were analyzed by mixed lymphocyte reaction.Cytokine expression was detected by ELISA.The apoptosis-related proteins of iPSCs-DCs and SN-iPSCs-DCs were analyzed by western blotting.The induced immunotolerance of SN-iPSCs-DCs was evaluated by treating recipient Balb/c skin graft mice.Statistical evaluation of graft survival was performed using Kaplan–Meier curves.RESULTS Both iPSCs-imDCs and SN-iPSCs-imDCs were successfully obtained,and their biological characteristics and ability to induce immunotolerance were compared.SN-iPSCs-imDCs exhibited higher CD11c levels and lower CD80 and CD86 levels compared with iPSCs-imDCs.Reduced major histocompatibility complex II expression,worse T-cell stimulatory function,higher Treg cell proliferative function and stronger endocytotic capacity were observed with SN-iPSCs-imDCs(P<0.05).The levels of interleukin(IL)-2,IL-12,interferon-γin SN-iPSCs-imDCs were lower than those in iPSCs-imDCs,whereas IL-10 and transforming growth factor-βlevels were higher(P<0.05).The apoptosis rate of these cells was significantly higher(P<0.05),and the expression levels of cleaved caspase3,Bax and cleaved poly(ADP-ribose)polymerase were higher after treatment with lipopolysaccharides,but Bcl-2 was reduced.In Balb/c mice recipients immunized with iPSCsimDCs or SN-iPSCs-imDCs 7 d before skin grafting,the SN-iPSCs-imDCs group showed lower ability to inhibit donor-specific CD4+T-cell proliferation(P<0.05)and a higher capacity to induce CD4+CD25+FoxP3+Treg cell proliferation in the spleen(P<0.05).The survival span of C57bl/6 skin grafts was significantly prolonged in immunized Balb/c recipients with a donor-specific pattern.CONCLUSION This study demonstrated that SN-iPSCs-imDCs have potential applications in vitro and in vivo for induction of immunotolerance following organ transplantation.

Role of maternal-fetal immune tolerance in the establishment and maintenance of pregnancy

Normal pregnancy is a contradictory and complicated physiological process.Although the fetus carries the human leukocyte antigen(HLA)inherited from the paternal line,it does not cause maternal immune rejection.As the only exception to immunological principles,maternal-fetal immune tolerance has been a reproductive immunology focus.In early pregnancy,fetal extravillous trophoblast cells(EVTs)invade decidual tissues and come into direct contact with maternal decidual immune cells(DICs)and decidual stromal cells(DSCs)to establish a sophisticated maternal-fetal crosstalk.This study reviews previous research results and focuses on the establishment and maintenance mechanism of maternal-fetal tolerance based on maternal-fetal crosstalk.Insights into maternal-fetal tolerance will not only improve understanding of normal pregnancy but will also contribute to novel therapeutic strategies for recurrent spontaneous abortion,pre-eclampsia,and premature birth.

Low-dose immune tolerance induction for severe hemophilia A inhibitor patients:Immunosuppressants are generally not necessary for inhibitor-titer below 200 BU/mL

Importance:It remained unclear that the efficacy comparison between low-dose immune tolerance induction(LD-ITI)incorporating immunosuppressants(IS)when severe hemophilia A(SHA)patients had inhibitor-titer≥200 Bethesda Units(BU)/mL(LD-ITI-IS^(200) regimen)and LD-ITI combining with IS when SHA patients had inhibitor-titer≥40 BU/mL(LD-ITI-IS^(40) regimen).Objective:To compare the efficacy of the LD-ITI-IS^(200) regimen with that of the LD-ITI-IS^(40) regimen for SHA patients with high-titer inhibitors.Methods:A prospective cohort study on patients receiving LD-ITI-IS^(200) compared to those receiving LD-ITI-IS^(40) from January 2021 to December 2023.Both received LD-ITI[FVIII 50 IU/kg every other day].IS(rituximab+prednisone)was added when peak inhibitor tier≥200 BU/mL in the LD-ITI-IS^(200) regimen and≥40 BU/mL in the LD-ITI-IS^(40) regimen.Success is defined as a negative inhibitor plus FVIII recovery≥66%of the expected.Results:We enrolled 30 patients on LD-ITI-IS^(200) and 64 patients on LD-ITI-IS^(40),with similar baseline clinical characteristics.A lower IS-use rate was discovered in the LD-ITI-IS^(200) regimen compared to the LD-ITI-IS^(40) regimen(30.0%vs.62.5%).The two regimens(LD-ITI-IS^(200) vs.LD-ITI-IS^(40))had similar success rate(70.0%vs.79.7%),median time to success(9.4 vs.10.6 months),and annualized bleeding rate during ITI(3.7 vs.2.8).The cost to success was lower for LD-ITI-IS^(200) than for LD-ITI-IS^(40)(2107 vs.3256 US Dollar/kg).Among patients with peak inhibitor-titer 40-199 BU/mL,10 non-IS-using(on LD-ITI-IS^(200) regimen)and 28 IS-using(on LD-ITI-IS^(40) regimen)had similar success rates(70.0%vs.78.6%)and time to success(9.0 vs.8.8 months).Interpretation:In LD-ITI,IS are not necessary for inhibitor titer<200 BU/mL.

Complex regulatory effects of gut microbial short-chain fatty acids on immune tolerance and autoimmunity

Immune tolerance deletes or suppresses autoreactive lymphocytes and is established at multiple levels during the development,activation and effector phases of T and B cells.These mechanisms are cell-intrinsically programmed and critical in preventing autoimmune diseases.We have witnessed the existence of another type of immune tolerance mechanism that is shaped by lifestyle choices,such as diet,microbiome and microbial metabolites.Short-chain fatty acids(SCFAs)are the most abundant microbial metabolites in the colonic lumen and are mainly produced by the microbial fermentation of prebiotics,such as dietary fiber.This review focuses on the preventive and immunomodulatory effects of SCFAs on autoimmunity.The tissue-and disease-specific effects of dietary fiber,SCFAs and SCFA-producing microbes on major types of autoimmune diseases,including type I diabetes,multiple sclerosis,rheumatoid arthritis and lupus,are discussed.Additionally,their key regulatory mechanisms for lymphocyte development,tissue barrier function,host metabolism,immunity,autoantibody production,and inflammatory effector and regulatory lymphocytes are discussed.The shared and differential effects of SCFAs on different types and stages of autoimmune diseases are discussed.

Mechanisms of Immune Tolerance and Inflammation via Gonadal Steroid Hormones in Preterm Birth

In 2019,preterm births(PTB)accounted for approximately 0.66 million deaths globally.PTB is also associated with a significantly higher risk of mortality and long-term complications for newborns.Long-term studies associated several factors,including disruption of immune tolerance and inflammation,with PTB.However,the pathogenesis of PTB remains unclear.Gonadal steroid hormones are critical for pregnancy maintenance and regulation of immune and inflammatory responses.However,it is not clear how unbalanced gonadal steroid hormones,such as imbalanced estrogen/androgen or estrogen/progesterone contribute to PTB.In this review,we discuss how gonadal steroid hormones mediate dysfunction in immune tolerance and inflammatory responses,which are known to promote the occurrence of PTB,and provide insight into PTB prediction.

Increased leakage of brain antigens after traumatic brain injury and effect of immune tolerance induced by cells on traumatic brain injury

Background Although traumatic brain injury can lead to opening the blood-brain barrier and leaking of blood substances （including water） into brain tissue, few studies of brain antigens leaking into the blood and the pathways have been reported. Brain antigens result in damage to brain tissues by stimulating the immune system to produce anti-brain antibodies, but no treatment has been reported to reduce the production of anti-brain antibodies and protect the brain tissue. The aim of the study is to confirm the relationship between immune injury and arachnoid granulations following traumatic brain injury, and provide some new methods to inhibit the immune injury.Methods In part one, methylene blue was injected into the rabbits’ cisterna magna after traumatic brain injury, and concentrations of methylene blue and tumor necrosis factor （TNF）-α in blood were detected to determine the permeability of arachnoid granulations. In part two, umbilical cord mesenchymal stem cells and immature dendritic cells were injected into veins, and concentrations of interleukin 1 （IL-1）, IL-10, interferon （IFN）-γ, transforming growth factor （TGF）-β, anti-brain antibodies （ABAb）, and IL-12 were measured by ELISA on days 1, 3, 7, 14 and 21 after injury, and the numbers of leukocytes in the blood were counted. Twenty-one days after injury, expression of glutamate in brain tissue was determined by immunohistochemical staining, and neuronal degeneration was detected by H＆E staining. Results In part one, blood concentrations of methylene blue and TNF-α in the traumatic brain injury group were higher than in the control group （P 〈0.05）. Concentrations of methylene blue and TNF-α in the trauma cerebrospinal fluid （CSF） injected group were higher than in the control cerebrospinal fluid injected group （P 〈0.05）. In part two, concentrations of IL-1, IFN-γ, ABAb, IL-12, expression of glutamate （Glu）, neuronal degeneration and number of peripheral blood leukocytes were lower in the group with cell treatment compared to the control group. IL-10 and TGF-β were elevated compared to the control group. Conclusions Traumatic brain injury can lead to stronger arachnoid granulations （AGs） permeability; umbilical cord mesenchymal stem cells and immature dendritic cells can induce immune tolerance and reduce inflammation and anti-brain antibodies to protect the brain tissue.

An experimental study on thymus immune tolerance to treat surgical brain injury

Background Many researches demonstrate that the secondary brain injury which is caused by autoimmune attack toward brain antigens plays an important role in surgical brain injury （SBI）.Although traditional immunosuppression can reduce autoimmune attack,it will lower the body immunity.Immune tolerance,by contrast,not only does not lower the body immunity,but also could lighten autoimmunity.This study used thymus tolerance to develop an immune system that is tolerant to autologous cerebrospinal fluid （CSF） and autologous brain tissue so that autoimmune injury can be suppressed following the disruption of the blood-brain barrier,thereby reducing brain damage.Methods Eighty experimental rabbits were divided into five groups by random number table method：16 in SBI group （group A）,16 in SBI＋CSF drainage group （group B）,16 in SBI＋CSF drainage＋PBS injection group （group C）,16 in SBI＋CSF drainage＋CSF intrathymic injection group （group D）,and 16 in SBl＋brain homogenate intrathymic injection group （group E）.Rabbits＆#39; CSF was drained in group B; was drained and injected PBS into thymus in group C; was drained and injected CSF into thymus in group D; and was injected brain homogenate in group E.Half of the rabbits in each group were phlebotomized on 1st,3rd,7th,and 14th days to observe the changes in IL-I,TGF-β by ELISA test,and CD4CD25 regulatory T cells ratio by flow cytometry,and in other animals brain tissues were taken on 7th day for exploring FasL expression by RT-PCR.The least significant difference （LSD） test was used to make paired comparisons; P ＜0.05 was considered statistically significant.Results The levels of FasL,TGF-β,and the ratios of CD4CD25 regulatory T cells in groups D and E were apparently higher than those in other three groups （P ＜0.05）.Likewise,the levels of IL-1 in these two groups were lower than the other three groups （P ＜0.05）.Moreover,the ratios of CD4CD25 regulatory T cells and the levels of TGF-β in groups B and C were higher than those in group A,but the level of IL-1 was lower than that in group A （P ＜0.05）.There was no significant difference between groups B and C,and groups D and E.Conclusion Thymic injection of CSF and brain homogenate may be able to reduce inflammation after SBI,so thymus immune tolerance may be a useful therapy to treat SBI.

Transcriptional and epigenetic regulation of immune tolerance:roles of the NF-κB family members

Immune tolerance is a highly regulated state and involves diverse mechanisms.Central to the induction of tolerance is the targeted modulation of T-cell activities(both effector and regulatory),in which transcription factors play a significant role.The nuclear factor kappa-B(NF-κB)family is a family of transcription factors that not only are critically involved in diverse T-cell responses but also are regulated by many mechanisms to maintain tolerance and T-cell homeostasis.NF-κB,as a transcription factor,has been extensively studied in recent decades,and the molecular mechanisms that regulate NF-κB activities have been well documented.However,recent studies have revealed exciting new roles for NF-κB;in addition to its transcriptional activity,NF-κB can also activate diverse epigenetic mechanisms that mediate extensive chromatin remodeling of target genes to regulate T-cell activities.In this review article,we highlight recent discoveries and emerging opportunities in targeting NF-κB family members as well as their associated chromatin modifiers in the induction of immune tolerance and in the clinical treatment of immune diseases.

Immune Tolerance Therapy： A New Method for Treatment of Traumatic Brain Injury

Objective： Due to the special anatomical structure and pathophysiological mechanism of the central nervous system （CNS）, there is a big difference between the repair of brain injury and other systems of the body. More and more evidence shows that targetedly reducing the autoimmune response of brain tissue without affecting the immune function in other parts of the body will be the best optimized treatment for brain injury. Data Sources： This review was based on data in articles published in PubMed up to June 5,2017, with the following keywords： ＂immune tolerance＂, ＂traumatic brain injury＂, and ＂central nervous system＂. Study Selection： Original articles and critical reviews on immune tolerance and brain damage were selected for this review. References of the retrieved articles were also screened to search for potentially relevant papers. Results： The CNS is isolated from the immune system through the blood-brain barrier. After brain injury, brain antigens are released into the systemic circulation to induce damaging immune responses. Immune tolerance can effectively reduce the brain edema and neurological inflammatory response after brain injury, which is beneficial to the recovery of neurological function. The clinical application prospect and theoretical research value of the treatment of immune tolerance on traumatic brain inj ury （TBi） is worth attention. Conclusions： The establishment of immune tolerance mechanism has a high clinical value in the treatment of TBI. It opens up new opportunities for the treatment of brain damage.

Histone methyltransferase Nsd2 ensures maternal-fetal immune tolerance by promoting regulatory T-cell recruitment

Regulatory T cells(Tregs)are fundamentally important for maintaining systemic immune homeostasis and are also required for immune tolerance at the maternal-fetal interface during pregnancy.Recent studies have suggested that epigenetic regulation is critically involved in Treg development and function.However,the role of H3K36me has not yet been investigated.Here,we found that the H3K36me2 methyltransferase Nsd2 was highly expressed in Tregs.Although loss of Nsd2 did not impair systemic Treg development or function,the level of Tregs at the maternal-fetal interface was significantly decreased in pregnant Nsd2 conditional knockout mice.Consequently,maternal-fetal immune tolerance was disrupted in the absence of Nsd2 in Tregs,and the pregnant mice showed severe fetal loss.Mechanistically,Nsd2 was found to upregulate CXCR4 expression via H3K36me2 modification to promote Treg cell recruitment into the decidua and suppress the anti-fetal immune response.Overall,our data identified Nsd2 as a critical epigenetic regulator of Treg recruitment for maternal-fetal tolerance.

Cytokine regulation of immune tolerance

The immune system provides defenses against invading pathogens while maintaining immune tolerance to self-antigens.This immune homeostasis is harmonized by the direct interactions between immune cells and the cytokine environment in which immune cells develop and function.Herein,we discuss three non-redundant paradigms by which cytokines maintain or break immune tolerance.We firstly describe how anti-inflammatory cytokines exert direct inhibitory effects on immune cells to enforce immune tolerance,followed by discussing other cytokines that maintain immune tolerance through inducing CD_(4)^(+) Foxp_(3)^(+) regulatory T cells(Tregs),which negatively control immune cells.Interleukin(IL)-2 is the most potent cytokine in promoting the development and survival of Tregs,thereby mediating immune tolerance.IL-35 is mainly produced by Tregs,but its biology function remains to be defi ned.Finally,we discuss the actions of proinflammatory cytokines that breach immune tolerance and induce autoimmunity,which include IL-7,IL-12,IL-21,and IL-23.Recent genetic studies have revealed the role of these cytokines(or their cognate receptors)in susceptibility to autoimmune diseases.Taken together,we highlight in this review the cytokine regulation of immune tolerance,which will help in further understanding of human diseases that are caused by dysregulated immune system.

Immune tolerance induced by immune-homeostatic particles

Autoimmune diseases,induced by dysfunction of the adaptive immune system,are the common disease categories worldwide.Recently,regulatory T cells(Tregs)enhancing therapies have been demonstrated to treat autoimmune diseases,which could induce immune tolerance to protect cells and tissues from self-attacking of the immune system.However,their widespread application is limited by complex manufacturing process,long production period and high cost.Herein,we give a perspective of immune-homeostatic particles as immune regulators to induce antigen-specific Tregs for treating autoimmune diseases.Disease-specific autoantigen is loaded into the particle to induce Tregs differentiation after release.In addition,the surface of the particles is decorated by specific ligands that could bind and trigger apoptosis of activated T cells,thereby impressing the overreacted immune system.Furthermore,liver sinusoidal endothelial cells(LSEC)-targeting particles are developed to stimulate CD4^(+)T cells differentiation into Tregs.We believe that the immune-homeostatic particles have great potential in autoimmune diseases treatment and are valuable in various immune-related disease treatments.

Facing challenges with hope:universal immune cells for hematologic malignancies

Many patients have achieved a favorable overall survival rate since allogenic hematopoietic stem cell transplantation(allo-HSCT)has been widely implemented to treat hematologic malignancies.However,graft-versus-host disease(GVHD)and complications of immunosuppressive drugs after allo-HSCT are the main causes of non-relapse mortality and a poor quality of life.In addition,GVHD and infusion-induced toxicity still occur with donor lymphocyte infusions(DLIs)and chimeric antigen receptor(CAR)T-cell therapy.Because of the special immune tolerance characteristics and anti-tumor ability of universal immune cells,universal immune cell therapy may strongly reduce GVHD,while simultaneously reducing tumor burden.Nevertheless,widespread application of universal immune cell therapy is mainly restricted by poor expansion and persistence efficacy.Many strategies have been applied to improve universal immune cell proliferation and persistence efficacy,including the use of universal cell lines,signaling regulation and CAR technology.In this review we have summarized current advances in universal immune cell therapy for hematologic malignancies with a discussion of future perspectives.

Gastric cancer liver metastasis will reduce the efficacy of immunotherapy

Immune checkpoint inhibitors augment the antitumor activity of T cells by inhibiting the negative regulatory pathway of T cells,leading to notable efficacy in patients with non-small cell lung cancer,melanoma,and other malignancies through immunotherapy utilization.However,secondary malignant liver tumors not only lower the liver's sensitivity to immunotherapy but also trigger systemic immune suppression,resulting in reduced overall effectiveness of immune therapy.Patients receiving immunotherapy for non-small cell lung cancer and melanoma experience reduced response rates,progression-free survival,and overall survival when secondary malignant tumors develop in the liver.Through Liu's retrospective analysis,valuable insights are provided for the future clinical management of these patients.Therefore,in patients with gastric cancer(GC),the occurrence of liver metastasis might be indicative of reduced efficacy of immuno-therapy.Overcoming liver immune tolerance mechanisms and their negative impacts allows for the potential benefits of immunotherapy in patients with GC and liver metastasis.INTRODUCTION Gastric cancer(GC)ranks among the prevalent malignancies affecting the digestive system globally.Based on the latest epidemiological data[1,2],it holds the fifth position for incidence and the fourth position for mortality among all malignant tumors.GC cases and fatalities in China make up roughly half of the worldwide figures.Earlier investigations[3]have demonstrated that the median overall survival(mOS)among advanced GC patients left untreated typically ranges from 3 to 4 months.Systemic chemotherapy recipients often experience a mOS of around one year,accompanied by a marked improvement in the quality of life among patients with advanced GC.The mainstay of treatment for advanced GC patients involves chemotherapeutic medications such as fluoropyrimidines,platinum compounds,and taxanes.However,their efficacy in tumor control is constrained by acquired resistance and primary resistance.The rise of personalized precision therapy has propelled immunotherapy into the spotlight as a crucial component of comprehensive treatment[4].By blocking the negative regulatory pathways of T cells,immune checkpoint inhibitors(ICIs)boost the anti-tumor effect of T cells.Immunotherapy has brought about significant therapeutic benefits for patients diagnosed with non-small cell lung cancer,melanoma,and related illnesses[5,6],instilling newfound hope in those with advanced GC[7].However,phase III clinical trial data[8-12]reveals that the incorporation of immunotherapy into chemotherapy regimens improves overall survival(OS)outcomes for patients with advanced GC.The liver's immune-exempt nature renders it less responsive to immunotherapy when secondary malignant tumors are present,fostering systemic immune suppression and yielding unfavorable outcomes in immune therapy[13-15].In retrospective research[16-20]pertaining to non-small cell lung cancer and melanoma,it has been observed that the presence of secondary liver malignancies may lower the response rate,progression-free survival(PFS),and OS rates in patients treated with immunotherapy,independent of factors such as tumor mutation burden and PD-L1 expression.Despite this,there is a paucity of studies examining whether the existence of secondary malignant liver tumors affects the effectiveness of immunotherapy in patients diagnosed with advanced HER-2 negative GC.

Consideration on immunotherapy of liver metastases of malignant tumors

In this editorial,we comment on the article“Analysis of the impact of immuno-therapy efficacy and safety in patients with gastric cancer and liver metastasis”by Liu et al that was published in the recent issue of the World Journal of Gastroin-testinal Surgery.It has prompted us to think and summarize some thoughts on immunotherapy for malignant tumor liver metastasis.Immunotherapy plays a crucial role in the treatment of malignant tumors;however,the presence of liver metastases in advanced tumors may impact its efficacy.Although patients with liver metastases can still benefit from immunotherapy,multiple clinical studies have indicated that,compared to other sites of metastasis,liver metastases may diminish the effectiveness of immunotherapy.The efficacy of immune checkpoint inhibitors in patients with liver metastases often fails to reach the ideal level,primarily due to the liver metastases exploiting the host's peripheral immune to-lerance mechanisms to promote systemic CD8(+)T cell exhaustion,resulting in a systemic immune-tolerant environment.This article aims to summarize the reasons for the decreased efficacy of immunotherapy following liver metastasis in various malignant tumors and propose potential clinical strategies for manage-ment.