Association of Graves’ disease and Graves’ ophthalmopathy with the polymorphisms in promoter and exon 1 of cytotoxic T lymphocyte associated antigen-4 gene

Objective: To investigate the association of Graves’ disease and Graves’ ophthalmopathy with the C/T transition polymorphism at position –318 of promoter and the A/G transition polymorphism at position 49 of exon 1 within cytotoxic T lymphocyte associated antigen-4 (CTLA-4) gene. Methods: Thirty-three patients with ophthalmopathy of Graves’ disease, fifty-six Graves’ patients without ophthalmopathy and sixty normal subjects as control were involved in the present case-control study. The polymorphisms were evaluated by polymerase chain reaction fragment length polymorphism (PCR-RFLP). Com-parisons were made of gene frequencies and allele frequencies between the groups. Results: The gene frequencies of CT and allele frequencies of T were much higher in Graves’ patients with ophthalmopathy than that in the group without ophthalmopathy (P=0.020, P=0.019). The gene frequencies of GG and allele frequencies of G in patients with Graves’ disease were significantly increased as compared with control group (P=0.008, P=0.007). The data suggest that smokers with Graves’ disease seemed to be more predisposed to ophthalmopathy than non-smokers (P=0.018). Conclusion: Our results suggest that an allele of T at position –318 of promoter is associated with genetic susceptibility to Graves’ ophthalmopathy while an allele of G at position 49 of exon 1 is associated with genetic susceptibility to Graves’ disease instead. Smoking is believed to be a major risk factor for ophthalmo-pathy.

Effect of cytotoxic T-lymphocyte antigen-4,TNF-alpha polymorphisms on osteosarcoma: evidences from a meta-analysis

Objective： Previous studies have investigated the role of cytotoxic T-lymphocyte antigen-4 （CTLA-4） and tumor necrosis factor-alpha （TNF-a） in carcinogenesis of osteosarcoma, but their results were inconsistent. We aimed to clarify the associations between CTLA-4, TNF-a polymorphism and osteosarcoma risk by using meta-analysis. Methods： We searched relevant studies without language restriction in PubMed, EMbase, Cochrane Library, Google Scholar databases, Chinese National Knowledge Infrastructure （CNKI） and conference literature in humans published prior to March 2013. The strengths of the associations between genetic variants and osteosarcoma risk were estimated by odds ratio （OR） with 95% confidence interval （95% CI）. Results： A total of seven studies with 1,198 osteosarcoma patients and 1,493 controls were selected. Four studies were eligible for CTLA-4 （1,003 osteosarcoma and 1,162 controls）, and three studies for TNF-a （195 osteosarcoma and 331 controls）. Pooled results showed that rs231775 polymorphism of CTLA-4 was associated with osteosarcoma risk （GG vs. AA： OR=1.63, 95% CI=1.24-2.13; GG ＋ GA vs. AA： OR=1.56, 95% CI=1.21-2.01; AA ＋ GA vs. GG： OR=0.83, 95% CI=0.71-0.97; G vs. A： OR=1.21, 95% CI=1.08-1.36）. No significant heterogeneity was observed across the studies. No significant associations were found between rs5742909 polymorphism of CTLA-4 or rs1800629 polymorphism of TNF-a and osteosarcoma risk. Conclusions： These results suggest that the rs231775 polymorphism of CTLA-4 may play an important role in carcinogenesis of osteosarcoma.

Advanced cervix cancer patient with chemotherapy-induced grade IV myelosuppression achieved complete remission with cadonilimab:A case report

BACKGROUND The prognosis for patients with advanced metastatic cervix cancer(MCC)is poor,and this disease continues to pose a considerable therapeutic challenge.Despite the administration of first-line regimens consisting of cisplatin,paclitaxel,and bevacizumab,survival rates for patients with metastasis remain poor.The emergence of bispecific antibodies(BsAbs)offers a novel treatment option for patients diagnosed with MCC.CASE SUMMARY In this report,we present a patient with MCC who was treated with cadonilimab monotherapy at a dose of 6 mg/kg every two weeks after chemotherapy was proven to be intolerable.The patient exhibited a sustained complete response for a duration of 6 months,demonstrating an optimistic outlook.CONCLUSION This case illustrates the considerable efficacy of cadonilimab for treating advanced MCC.Therefore,BsAb therapy is a promising strategy for effectively treating patients with advanced MCC and should be considered as an option when patients are intolerant to standard chemotherapy.

CD28/CTLA-4/B7 and CD40/CD40L costimulation and activation of regulatory T cells

Costimulatory signals are crucial for T cell activation. Attempts to block costimulatory pathways have been effective in preventing unwanted immune reactions. In particular, blocking the CD28/cytotoxic T lymphocyte antigen(CTLA)-4/B7 interaction(using CTLA-4Ig) and the CD40/CD40 L interaction(using anti-CD40 L antibodies) prevents T cell mediated autoimmune diseases, transplant rejection and graft vs host disease in experimental models. Moreover, CTLA-4Ig is in clinical use to treat rheumatoid arthritis(abatacept) and to prevent rejection of renal transplants(belatacept). Under certain experimental conditions, this treatment can even result in tolerance. Surprisingly, the underlying mechanisms of immune modulation are still not completely understood. We here discuss the evidence that costimulation blockade differentially affects effector T cells(Teff) and regulatory T cells(Treg). The latter are required to control inappropriate and unwanted immune responses, and their activity often contributes to tolerance induction and maintenance. Unfortunately, our knowledge on the costimulatory requirements of Treg cells is very limited. We therefore summarize the current understanding ofthe costimulatory requirements of Treg cells, and elaborate on the effect of anti-CD40 L antibody and CTLA-4Ig treatment on Treg cell activity. In this context, we point out that the outcome of a treatment aiming at blocking the CD28/CTLA-4/B7 costimulatory interaction can vary with dosing, timing and underlying immunopathology.

Combined immune checkpoint inhibitors of CTLA4 and PD-1 for hepatic melanoma of unknown primary origin: A case report

BACKGROUND Melanoma is uncommonly found in lymph nodes,subcutaneous tissue,or visceral organs without a primary lesion,where it is identified as metastatic melanoma with unknown primary(MUP).Hepatic MUP is extremely rare and has a poor prognosis.There is limited information on its pathogenesis,clinical and imaging features,and pathological findings.There are no guidelines for the use of immune checkpoint inhibitors(ICIs)in hepatic MUP,and the treatment outcome has rarely been reported.CASE SUMMARY A 42-year-old woman presented to our hospital with hepatic tumors found incidentally during a routine check-up.Contrast-enhanced abdominal computerized tomography showed multiple mass lesions in the liver.Pathological results revealed melanoma,which was confirmed by immunohistochemical staining for HMB-45(+),Melan-A(+),S-100(+),and SOX10(+).There was no evidence of primary cutaneous,ocular,gastrointestinal,or anal lesion on a comprehensive examination.The patient was diagnosed with hepatic MUP.She received combined antibodies against cytotoxic T-lymphocyte-associated antigen 4(CTLA-4,ipilimumab)and programmed death protein-1(PD-1,nivolumab).She died of hepatic failure 9 mo after hepatic MUP was diagnosed.This the first case of hepatic MUP treated with combined ipilimumab and nivolumab,who showed better outcome than previous cases.CONCLUSIONCombined ICIs of PD-1 and CTLA-4 may be considered as the first-line therapyfor patients with hepatic MUP.

Association between the cytotoxic T-lymphocyte antigen-4 polymorphisms and breast cancer risk and prognosis

Aim:The aim was to evaluate the potential infl uences of cytotoxic T-lymphocyte antigen-4(CTLA-4)gene polymorphisms on breast cancer risk,the distribution of CTLA-4 single nucleotide polymorphisms(1661AG)in breast cancer patients and control subjects was investigated.Methods:In this case-control study,100 patients with breast cancer as case group and 100 healthy participants as a control group were compared.Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism method.Demographic characteristics of the study population,as well as tumor size,tumor grade and stage were collected in a questionnaire designed for this study.The collected data were statistically analyzed by SPSS-16.0(SPSS Inc.,Chicago,USA)predictive analytic software using the Chi-square test.Results:The mean age of women was 43.42±13.1 years.The AA genotype was frequent in case group(43%)whereas the AG genotype was found more in the control group(69%).There was no signifi cant relationship between the studied polymorphisms and the grade,stage and size of the tumor,nor between the studied polymorphisms and estrogen receptor,progesterone receptor and lymph node involvement(P>0.05).Signifi cant association between the studied polymorphisms and breast cancer metastases was found(P=0.02).Conclusion:According to the results of the study,the AA genotype is associated with breast cancer,but none of the studied gene polymorphisms is associated with prognostic factors such as tumor stage,grade or size.

Advances in immunotherapy for treatment of lung cancer

Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 （PD-1） and its ligand （PD-L1）, on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab~ another anti PD-1 antibod）5 has received FDA breakthrough therapy designation for treatment of non-small cell lung cancer （NSCLC）, supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months.

Specific CD8^+ T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis

Hepatocellular carcinoma (HCC), chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are characterized by exhaustion of the specific CD8+ T cell response. This process involves enhancement of negative co-stimulatory molecules, such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), 2B4, Tim-3, CD160 and LAG-3, which is linked to intrahepatic overexpression of some of the cognate ligands, such as PD-L1, on antigen presenting cells and thereby favouring a tolerogenic environment. Therapies that disrupt these negative signalling mechanisms represent promising therapeutic tools with the potential to restore reactivity of the specific CD8+ T cell response. In this review we discuss the impressive in vitro and in vivo results that have been recently achieved in HCC, CHB and CHC by blocking these negative receptors with monoclonal antibodies against these immune checkpoint modulators. The article mainly focuses on the role of CTLA-4 and PD-1 blocking monoclonal antibodies, the first ones to have reached clinical practice. The humanized monoclonal antibodies against CTLA-4 (tremelimumab and ipilimumab) and PD-1 (nivolumab and pembrolizumab) have yielded good results in testing of HCC and chronic viral hepatitis patients. Trelimumab, in particular, has shown a significant increase in the time to progression in HCC, while nivolumab has shown a remarkable effect on hepatitis C viral load reduction. The research on the role of ipilimumab, nivolumab and pembrolizumab on HCC is currently underway.

Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors

Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-infiltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T-ceU infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clinical trials to test the combination are currently ongoing.

Emergence of immunotherapy as a novel way to treat hepatocellular carcinoma

Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.

Progress in immunotherapy for small cell lung cancer

Small-cell lung cancer(SCLC)is a special type of lung cancer that belongs to highly aggressive neuroendocrine tumors.At present,radiotherapy and chemotherapy remain the mainstay of treatment for SCLC.Progress in targeted therapies for SCLC with driver mutations has been slow,and these therapies are still under investigation in preclinical or early-phase clinical trials,and research on antiangiogenic tyrosine kinase inhibitors(e.g.,anlotinib)has achieved some success.Immunotherapy is becoming an important treatment strategy for SCLC after radiotherapy and chemotherapy.In this article we review the recent advances in immunotherapy for SCLC.

Faecal microbiota transplantation enhances efficacy of immune checkpoint inhibitors therapy against cancer

Even though immune checkpoint inhibitors(ICIs)are effective on multiple cancer types,there are still many non-responding patients.A possible factor put forward that may influence the efficacy of ICIs is the gut microbiota.Additionally,faecal microbiota transplantation may enhance efficacy of ICIs.Nevertheless,the data available in this field are insufficient,and relevant scientific work has just commenced.As a result,the current work reviewed the latest research on the association of gut microbiota with ICI treatments based on anti-programmed cell death protein 1 antibody and anti-cytotoxic T-lymphocyte-associated protein 4 antibody and explored the therapeutic potential of faecal microbiota transplantation in combination with ICI therapy in the future.

Immunotherapies for well-differentiated grade 3 gastroenteropancreatic neuroendocrine tumors:A new category in the World Health Organization classification

According to the 2019 World Health Organization(WHO)classification,welldifferentiated grade 3(G3)gastroenteropancreatic(GEP)neuroendocrine tumors(NETs)are a new category of cancer of the digestive system.G3 GEP-NET research and treatment are not as robust as those of lower grade(G1/2)NETs and poorly differentiated neuroendocrine carcinomas(NECs).Previously,the management of high-grade NETs was mainly based on NEC therapies,as highgrade NETs were classified as NECs under the previous WHO classification.Despite this,G3 GEP-NETs are significantly less responsive to platinum-based chemotherapy regimens than NECs,due to their distinct molecular pathogenesis and course of pathological grade transition.Patients with advanced G3 GEPNETs,who have progressed or are intolerant to chemotherapy regimens such as capecitabine plus temozolomide,have limited treatment choices.Immunotherapy has helped patients with a variety of cancers attain long-term survival through the use of immune checkpoint inhibitors.Immunotherapies,either alone or in combination with other therapies,do not have a clear function in the treatment of G3 GEP-NETs.Currently,the majority of immunotherapy studies,both prospective and retrospective,do not reliably differentiate G3 GEP-NETs from NECs.By contrast,a significant number of studies include non-GEP neuroendocrine neoplasms(NENs).Therefore,there is an urgent need to summarize and evaluate these data to provide more effective therapeutic approaches for patients with this rare tumor.The purpose of this mini-review was to screen and summarize information on G3 GEP-NETs from all studies on NENs immunotherapy.

Targeted immunotherapy for non-small cell lung cancer

Targeted therapies that deliver the expected anti-tumor effects while mitigating the adverse effects are taking the cancer world by storm. The need for such therapies in non-small cell lung cancer(NSCLC), where systemic cytotoxic chemotherapies still remain the backbone of management, is felt more than ever before. Runway success of immunotherapies such as Ipilimumab for melanoma has brought excitement among oncologists. Immune-based treatments are in various stages of evaluation for NSCLC as well. Immunotherapies using strategies of antigen based or cell based vaccines, and blocking immune checkpoints are of substantial interest. Meaningful clinical responses are yet to be reaped from these new treatment modalities.

Costimulatory blockade:A novel approach to the treatment of glomerular disease?

Costimulatory pathways(Cluster of differentiation 28,tumor necrosis factor-related,adhesion and T Cell Ig-and mucin-domain molecules) regulating the interactions between receptors on the T cells andtheir ligands expressed on several cell types,have a key role in controlling many immunological and non immunological processes.Indeed,accumulating evidence indicate that these molecules are involved in the pathogenesis of numerous conditions,such as allograft rejection,atherosclerosis,rheumatoid arthritis,psoriasis and renal diseases,including glomerulonephritis.Primary or secondary(i.e.,associated with infections,drugs or systemic diseases,such as systemic lupus erythematosus,diabetes,etc.) glomerulonephritis represent a group of heterogeneous diseases with different pathogenic mechanisms.Since costimulatory molecules,in particular CD80 and CD40,have been found to be expressed on podocytes in the course of different experimental and clinical glomerulonephritis,costimulation has been thought as a new therapeutic target for patients with glomerular diseases.However,although experimental data suggested that the blockade of costimulatory pathways is effective and safe in the prevention and treatment of glomerular diseases,clinical trials reported contrasting results.So,at this moment,there is not a strong evidence for the general use of costimulatory blockade as an alternative treatment strategy in patients with primary or secondary glomerulonephritis.Here,we critically discuss the current data and the main issues regarding the development of this innovative therapeutic approach.

Why natural killer cells in triple negative breast cancer?

The triple-negative subtype of breast cancer(TNBC)has the bleakest prognosis,owing to its lack of either hormone receptor as well as human epidermal growth factor receptor 2.Henceforth,immunotherapy has emerged as the front-runner for TNBC treatment,which avoids potentially damaging chemotherapeutics.However,despite its documented association with aggressive side effects and developed resistance,immune checkpoint blockade continues to dominate the TNBC immunotherapy scene.These immune checkpoint blockade drawbacks necessitate the exploration of other immunotherapeutic methods that would expand options for TNBC patients.One such method is the exploitation and recruitment of natural killer cells,which by harnessing the innate rather than adaptive immune system could potentially circumvent the downsides of immune checkpoint blockade.In this review,the authors will elucidate the advantageousness of natural killer cell-based immuno-oncology in TNBC as well as demonstrate the need to more extensively research such therapies in the future.

Diarrhoea in a patient with metastatic melanoma:Ipilimumab ileocolitis treated with infliximab

Administration of ipilimumab,a cytotoxic T-lymphocyte associated antigen-4-blocking monoclonal antibody,leads to enhancement of the anti-tumor T-cell respons and as a result shows a significant survival benefit in metastatic melanoma patients.Therefore patients are currently receiving this promising therapy as a secondline strategy.Unfortunately,by activation of the T-cell immune reponse,ipilimumab therapy may lead to an unwanted induction of different autoimmune phenomena.Diarrhoea and colitis occur in up to one third of patients.Here we present a case of ipilimumab induced ileocolitis which was successfully treated with infliximab,an anti-tumor necrosis factor monoclonal antibody,after corticosteroid therapy failure.Although formal trials are lacking,recently publicated series suggest that infusional therapy of infliximab is effective in ipilimumab induced ileocolitis.

Immune blockade inhibitors and the radiation abscopal effect in gastrointestinal cancers

The field of tumor immunology has produced in the recent years a revolution in cancer therapeutics putting an end in the long lasting frustration of investigators in the area stemming from largely unsuccessful strides to develop cancer vaccines. This progress has come from the introduction of immune checkpoint inhibitors, monoclonal antibodies blocking ligand/receptor pairs with inhibitory effects for immune cells. Through this blockade immune checkpoint blockers are able to ac-tivate the immune system and create an anti-tumoral effect. A significant sub-set of patients with various types of cancers such as melanoma, lung carcinomas and urothelial cancers benefit from treatment with these drugs and survivals have improved in some ca-ses. However other cancers are primarily resistant to immune blockers and secondary resistance is also the norm. Radiation therapy is often used in the palliative treatment of patients with advanced cancers and, in addition to the local effect in the irradiated field, it may in rare cases produce a systemic antitumor effect, termed "abscopal". This effect has been suggested to be produced by immune mechanisms. Thus an opportunity presents for a synergistic effect of immune stimulation between radiation and immune blockade inhibitors. The therapeutic opportunities presented with the combination of radiation and these drugs for gastrointestinal cancers will be discussed in this editorial overview.

Extremely high frequency of autoimmune-predisposing alleles in medieval specimens

The precise etiology and reasons for the increase in incidence of autoimmune disorders still remain unclear, and although both genetic and environmental factors have been proven to shape individual predisposition, it is not known which of the factors, if not both, is responsible for the boom observed during the last decades. In order to establish whether a higher frequency of autoimmune-predisposing alleles may explain this increase we took advantage of ancient DNA methodology to establish the genetic predisposition, conferred by cytotoxic T lymphocyte associated antigen-4 （CTLA4） ＋49A/G and human leukocyte antigens （HLA） DQBI^57, in population inhabiting Poland in the Middle Ages. After successful typing of 42 individuals from a 12th-14th＇s century archeological burial site, we found that frequencies of the predisposing alleles in the medieval population were higher than they are at present, suggesting thus that the recently observed incidence increase results most probably from factors of other than genetic nature.

Present and future of immune checkpoint blockade: Monotherapy to adjuvant approaches

Immune regulation of aggressive tumor growth is often outpaced by tumor up-regulation of ligands that inhibit effector immune responses through the activation of immune checkpoints. A few of such checkpoints include programmed death-1(PD-1), cytotoxic T lymphocyte associated antigen-4(CTLA-4), lymphocyte activation gene-3, T-cell immunoglobulin and mucin protein-3, Glucocorticoid-induced TNFR family-related receptor(GITR), and killer cell immunoglobulin like receptor. With the exception of GITR, after binding to their respective ligands these checkpoints induce down-modulation of immune responses to prevent autoimmunity. However, such immune mechanisms are co-opted by tumors to allow rapid tumor cell proliferation. Pre-clinical studies in antibody blockade of PD-1 and CTLA-4 have led to promising augmentation of effector immune responses in murine tumor models, and human antibodies against PD-1 and CTLA-4 alone or in combination have demonstrated tumor regression in clinical trials. The development of immune checkpoint blockade as a potential future immunotherapy has led to increasing interest in combining treatment modalities. Combination checkpoint blockade with chemotherapy and radiation therapy has shown synergistic effects in pre-clinical and clinical studies, and combination checkpoint blockade with bacterial vaccine vectors have produced increased effector immune responses in pre-clinical models. The future of immune checkpoint blockade may be as a powerful adjuvant alongside the current standard of care.