Dihydroartemisinin enhances cell apoptosis in diffuse large B cell lymphoma by inhibiting the STAT3 activity

Background:Dihydroartemisinin(DHA)is reported to be a potential anticancer agent,and the mechanisms underlying the effects of DHA on diffuse large B cell lymphoma however are still obscure.This study aimed to assess the antitumor effect of DHA on diffuse large B cell lymphoma cells and to determine the potential underlying mechanisms of DHA-induced cell apoptosis.Methods:Here,the Cell Counting Kit 8 assay was conducted to study cell proliferation.We performed Annexin V-FITC/propidium iodide staining,real-time polymerase chain reaction,and western blot analysis to analyze cell apoptosis and potential molecular mechanisms.Results:The results showed that DHA substantially suppressed cell proliferation and induced cell apoptosis in vitro in a time-and concentration-dependent fashion.Moreover,STAT3 activity could be inhibited after stimulation with DHA.Conclusion:These results imply that the underlying anti-tumoral effect of DHA may increase apoptosis in diffuse large B cell lymphoma cells via the STAT3 signaling pathway.In addition,DHA might be an effective drug for diffuse large B cell lymphoma therapy.

Efficacy of rituximab in gastric diffuse large B cell lymphoma patients

AIM:To evaluate retrospectively the efficacy of rituximab plus chemotherapy in gastric diffuse large B cell lymphoma(DLBCL).METHODS:Sixty patients(median age:58 years)with histologically confirmed gastric DLBCL treated at four Italian institutions between 2000 and 2007,were included in this analysis.Patients were selected by stage (Ⅰ-Ⅳ,Lugano staging system),European Cooperative Oncology Group performance status(0-2)and treatment strategies.Treatment strategies were chemotherapy alone(group A,n=30)[scheduled as cyclophosphamide,doxorubicin,vincristine and prednisone (CHOP)and CHOP-like],and chemotherapy combined with rituximab(group B,n=30).The primary end point of the study was complete response(CR)rate;the secondary end points were disease-free survival (DFS)at 5 years and overall survival(OS).RESULTS:Median follow-up was 62 mo(range:31102 mo).We observed a significant difference between the two groups(A vs B)in terms of CR[76.6%(23/30) vs 100%,P=0.04)and DFS at 5 years[73.3%(22/30) vs 100%,P=0.03).To date,19 group A(63.3%) patients are alive and 11 have died,while all group B patients are alive.No significant differences in toxicity were observed between the two groups.CONCLUSION:Rituximab in combination with chemotherapy improves CR rate,DFS and OS.Further prospective trials are needed to confirm our results.

Generation and selection of immunized Fab phage display library against human B cell lymphoma

The approval of using monoclonal antibodies as a targeted therapy in the management of patients with B cell lymphoma has led to new treatment options for this group of patients. Production ofmonoclonal antibodies by the traditional hybridoma technology is costly, and the resulting murine antibodies often have the disadvantage of triggering human anti-mouse antibody （HAMA） response. Therefore recombinant Fab antibodies generated by the phage display technology can be a suitable alternative in managing B cell lymphoma. In this study, we extracted total RNA from spleen cells of BALB/c mice immunized with human B lymphoma cells, and used RT-PCR to amplify cDNAs coding for the κ light chains and Fd fragments of heavy chains. After appropriate restriction digests, these cDNA fragments were successively inserted into the phagemid vector pComb3H-SS to construct an immunized Fab phage display library. The diversity of the constructed library was approximately 1.94× 10^7. Following five rounds of biopanning, soluble Fab antibodies were produced from positive clones identified by ELISA. From eight positive clones, FabC06, FabC21, FabC43 and FabC59 were selected for sequence analysis. At the level of amino acid sequences, the variable heavy domains （VH） and variable light domains （VL） were found to share 88-92% and 89-94% homology with sequences coded by the corresponding murine germline genes respectively. Furthermore, reactivity with membrane proteins of the B cell lymphoma was demonstrated by immunohistochemistry and western blotting. These immunized Fab antibodies may provide a valuable tool for further study of B cell lymphoma and could also contribute to the improvement of disease therapy.

New risk factors and new tendency for central nervous system relapse in patients with diffuse large B-cell lymphoma:a retrospective study

Background: In patients with difuse large B?cell lymphoma(DLBCL), central nervous system(CNS) relapse is uncom?mon but is nearly always fatal. This study aimed to determine the risk factors for CNS relapse in DLBCL patients and to evaluate the eicacy of rituximab and intrathecal chemotherapy prophylaxis for CNS relapse reduction.Methods: A total of 511 patients with newly diagnosed DLBCL treated at the Sun Yat?sen University Cancer Center between January 2003 and December 2012 were included in the study. Among these patients, 376 received R?CHOP regimen(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment, and 135 received CHOP regimen(cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment. Intrathe?cal chemotherapy prophylaxis(methotrexate plus cytarabine) was administered to those who were deemed at high risk for CNS relapse. In the entire cohort and in the R?CHOP set in particular, the Kaplan–Meier method coupled with the log?rank test was used for univariate analysis, and the Cox proportional hazards model was used for multivariate analysis. Diferences were evaluated using a two?tailed test, and P < 0.05 was considered signiicant.Results: At a median follow?up of 46 months, 25(4.9%) patients experienced CNS relapse. There was a trend of reduced occurrence of CNS relapse in patients treated with rituximab; the 3?year cumulative CNS relapse rates were 7.1% in CHOP group and 2.7% in R?CHOP group(P = 0.045). Intrathecal chemotherapy prophylaxis did not confer much beneit in terms of preventing CNS relapse. Bone involvement [hazard ratio(HR) = 4.21, 95% conidence interval(CI) 1.38–12.77], renal involvement(HR = 3.85, 95% CI 1.05–14.19), alkaline phosphatase(ALP) >110 U/L(HR = 3.59, 95% CI 1.25–10.34), serum albumin(ALB) <35 g/L(HR = 3.63, 95% CI 1.25–10.51), treatment with rituxi?mab(HR = 0.34, 95% CI 0.12–0.96), and a time to complete remission ≤ 108 days(HR = 0.22, 95% CI 0.06–0.78) were independent predictive factors for CNS relapse in the entire cohort. Bone involvement(HR = 4.44, 95% CI 1.08–18.35), bone marrow involvement(HR = 11.70, 95% CI 2.24–60.99), and renal involvement(HR = 10.83, 95% CI 2.27–51.65) were independent risk factors for CNS relapse in the R?CHOP set.Conclusions: In the present study, rituximab decreased the CNS relapse rate of DLBCL, whereas intrathecal chemo?therapy prophylaxis alone was not suicient for preventing CNS relapse. Serum levels of ALB and ALP, and the time to complete remission were new independent predictive factors for CNS relapse in the patients with DLBCL. In the patients received R?CHOP regimen, a trend of increased CNS relapse was found to be associated with extranodal lesions.

Role of Immune Microenvironmental Factors for Improving the IPI-related Risk Stratification of Aggressive B Cell Lymphoma

Objective To investigate the risk stratification of aggressive B cell lymphoma using the immune microenvironment and clinical factors. Methods A total of 127 patients with aggressive B cell lymphoma between 2014 and 2015 were enrolled in this study. CD4, Foxp3, CDS, CD68, CD163, PD-1, and PD-L1 expression levels were evaluated in paraffin-embedded lymphoma tissues to identify their roles in the risk stratification. Eleven factors were identified for further evaluation using analysis of variance, chi-square, and multinomial logistic regression analysis. Results Significant differences in 11 factors （age, Ann Arbor stage, B symptom, ECOG performance status, infiltrating CD8＋ T cells, PD-L1 expression, absolute blood monocyte count, serum lactate dehydrogenase, serum iron, serum albumin, and serum l^2-microglobulin） were observed among patient groups stratified by at least two risk stratification methods [International Prognostic Index （IPI）, revised IPI, and NCCN-IPI models] （P 〈 0.05）. Concordance rates were high （81.4%-100.0%） when these factors were used for the risk stratification. No difference in the risk stratification results was observed with or without the Ann Arbor stage data. Conclusion We developed a convenient and inexpensive tool for use in risk stratification of aggressive B cell lymphomas, although further studies on the role of immune microenvironmental factors are needed.

Manifestation of severe pneumonia in anti-PL-7 antisynthetase syndrome and B cell lymphoma:A case report

BACKGROUND Antisynthetase syndrome(ASS)is characterized by the presence of antisynthetase antibodies coupled with clinical findings such as fever,polymyositis-dermatomyositis and interstitial lung disease.It is,however,rare to observe ASS association with B cell lymphoma presenting severe pneumonia as the first clinical manifestation.CASE SUMMARY We evaluated a 59-year-old male patient who presented with cough with sputum,shortness of breath and fever for 13 d.A chest computed tomography radiograph revealed bilateral diffuse ground-glass infiltrates in both upper fields,left lingual lobe and right middle lobe.Initially,the patient was diagnosed with severe community-acquired pneumonia and respiratory failure.He was empirically treated with broad-spectrum antibiotics,without improvement.Further analysis showed an ASS panel with anti-PL7 antibodies.Besides,electromyography evaluation demonstrated a manifestation of myogenic damage,while deltoid muscle biopsy showed irregular muscle fiber bundles especially abnormal lymphocyte infiltration.In addition,bone marrow biopsy revealed high invasive B cell lymphoma.Thus,the patient was diagnosed with a relatively rare anti–PL7 antibody positive ASS associated with B cell lymphoma.CONCLUSION This case highlights that rapidly progressive lung lesions and acute hypoxemic respiratory failure associated with heliotrope rash and extremely high lactate dehydrogenase level should be considered as the characteristics of non-infectious diseases,especially ASS and B cell lymphoma.

Diagnosis and therapy of primary lung diffuse large B cell lymphoma： a case report

Objective： We studied the diagnosis and therapy of primary lung diffuse large B cell lymphoma （DLBCL）. Methods： Analysis the clinical manifestations, pathologic character and immunohistochemical character of one lung diffuse B cell lymphoma patent. Results： In visual observation, it＇s a gray irregular fobulated mass, section was gray, fish-like, and number of necrotic foci. Observed under the microscope, subepithelial respiratory center oocyte-like cells diffuse proliferative, infiltration in lung tissue. Immunohistochemistry： CD20 （＋）, CD79a （＋）, CD3 （-）, CD45RO （-）, PCK （-）. Conclusion： Diffuse large B cell lymphoma is the most common subtype in non-Hodgkin lymphoma, but the primary lung diffuse large B cell lymphoma is rare. This disease is lack of typical clinical manifestations, so easily misdiagnosed. The diagnosis of diffuse large B cell lymphoma should be based on pathology and immunohistochemistry.

Guillain-Barrésyndrome and hemophagocytic syndrome heralding the diagnosis of diffuse large B cell lymphoma:A case report

BACKGROUND Central nervous system(CNS)lesions and peripheral neuropathy are rare among patients with non-Hodgkin’s lymphoma(NHL).Lymphomatous infiltration or local oppression usually accounts for CNS or peripheral nerve lesions.The incidence of peripheral neuropathy was 5%.Guillain-Barrésyndrome(GBS)is rare and may occur in less than 0.3%of patients with NHL.Hemophagocytic syndrome(HPS)is a rare complication of NHL.It has been reported that 1%of patients with hematological malignancies develop HPS.Diffuse large B-cell lymphoma(DLBCL)combined with GBS has been reported in 10 cases.CASE SUMMARY We report the case of a 53-year-old man who was initially hospitalized because of abnormal feelings in the lower limbs and urinary incontinence.He was finally diagnosed with DLBCL combined with GBS and HPS after 16 d,which was earlier than previously reported.Immunoglobulin pulse therapy,dexamethasone,and etoposide were immediately administered.The neurological symptoms did not improve,but cytopenia was relieved.However,GBS-related clinical symptoms were relieved partially after one cycle of rituximab-cyclophosphamide,hydroxydaunorubicin,vincristine,and prednisone(R-CHOP)chemotherapy and disappeared after six cycles of R-CHOP.CONCLUSION GBS and HPS heralding the diagnosis of Epstein-Barr virus DLBCL are rare.Herein,we report a rare case of DLBCL combined with GBS and HPS,and share our clinical experience.Traditional therapies may be effective if GBS occurs before lymphoma is diagnosed.Rapid diagnosis and treatment of DLBCL are crucial.

Diffuse large B cell lymphoma originating from the maxillary sinus with skin metastases:A case report and review of literature

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is the most common type of malignant lymphoma(ML),accounting for 30%-40%of cases of non-Hodgkin’s lymphoma(NHL)in adults.Primary paranasal sinus lymphoma is a rare presentation of extranodal NHL that accounts for only 0.17%of all lymphomas.ML from the maxillary sinus(MS)is a particularly rare presentation,and is thus often difficult to diagnose.We have reported the first known case of DLBCL originating from the MS with rapidly occurrent multiple skin metastasis.CASE SUMMARY An 81-year-old Japanese man visited our hospital due to continuous pain for 12 d in the left maxillary nerve area.His medical history included splenectomy due to a traffic injury,an old right cerebral infarction from when he was 74-years-old,hypertension,and type 2 diabetes mellitus.A plain head computed tomography(CT)scan revealed a 3 cm×3.1 cm×3 cm sized left MS.On day 25,left diplopia and ptosis occurred,and a follow-up CT on day 31 revealed the growth of the left MS mass.Based on an MS biopsy on day 50,we established a definitive diagnosis of DLBCL,non-germinal center B-cell-like originating from the left MS.The patient was admitted on day 62 due to rapid deterioration of his condition,and a plain CT scan revealed the further growth of the left MS mass,as well as multiple systemic metastasis,including of the skin.A skin biopsy on day 70 was found to be the same as that of the left MS mass.We notified the patient and his family of the disease,and they opted for palliative care,considering on his condition and age.The patient died on day 80.CONCLUSION This case suggests the need for careful,detailed examination,and for careful follow-up,when encountering patients presenting with a mass.

Occurrence of MYD88L265P and CD79B mutations in diffuse large b cell lymphoma with bone marrow infiltration:A case report

BACKGROUNDOver the past 20 years,we have gained a deep understanding of the biologicalheterogeneity of diffuse large B cell lymphoma(DLBCL)and have developed arange of new treatment programs based on the characteristics of the disease,bringing us to the era of immune-chemotherapy.However,the effectiveness andmolecular mechanisms of targeted-immunotherapy remain unclear in DLBCL.Targeted-immunotherapy may be beneficial for specific subgroups of patients,thus requiring biomarker assessment.CASE SUMMARYHere,we report a case of MCD subtype DLBCL with MYD88L265P and CD79Bmutations,considered in the initial stage as lymphoplasmic lymphoma(LPL)orWaldenstrom macroglobulinemia(WM).Flow cytometry supported this view;however,the immunohistochemical results of the lymph nodes overturned theabove diagnosis,and the patient was eventually diagnosed with MCD subtypeDLBCL.The presence of a monoclonal IgM component in the serum and infiltrationof small lymphocytes with a phenotype compatible with WM into the bonemarrow led us to propose a hypothesis that the case we report may have transformedfrom LPL/WM.CONCLUSIONThis highlights the possible transformation from WM to DLBCL,CD79B mutationmay be a potential biomarker for predicting this conversion.

Disseminated soft tissue diffuse large B-cell lymphoma involving multiple abdominal wall muscles:A case report

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is the most common subtype of non�Hodgkin lymphoma,and patients with DLBCL typically present rapidly growing masses.Lymphoma involving muscle is rare and accounts for only 5%;furthermore,multiple muscles and soft tissue involvement of DLBCL is unusual.Due to unusual clinical manifestation,accurate diagnosis could be delayed.CASE SUMMARY A 61-year-old man complained of swelling,pain and erythematous changes in the lower abdomen.Initially,soft tissue infection was suspected,however,skin lesion did not respond to antibiotics.18Fluoro-2-deoxy-D-glucose(18F-FDG)positron emission tomography-computed tomography demonstrated FDG uptake not only in the skin and subcutaneous tissue of the abdomen but also in the abdominal wall muscles,peritoneum,perineum,penis and testis.DLBCL was confirmed by biopsy of the abdominal wall muscle and subcutaneous tissue.After intensive treatment including chemotherapy with rituximab,cyclophosphamide,doxorubicin,vincristine and prednisolone,central nervous system prophylaxis(intrathecal injection of methotrexate,cytarabine and hydrocortisone)and orchiectomy,he underwent peripheral blood stem cell mobilization for an autologous hematopoietic stem cell transplantation.Despite intensive treatment,the disease progressed rapidly and the patient showed poor outcome(overall survival,9 mo;disease free survival,3 mo).CONCLUSION The first clinical manifestation of soft tissue DLBCL involving multiple muscles was similar to the infection of the soft tissue.

Antitumor efficacy of multi-target in situ vaccinations with CpG oligodeoxynucleotides,anti-OX40,anti-PD1 antibodies,and aptamers

To overcome immune tolerance to cancer,the immune system needs to be exposed to a multi-target action intervention.Here,we investigated the activating effect of CpG oligodeoxynucleotides(ODNs),mesyl phosphoramidate CpG ODNs,anti-OX40 antibodies,and OX40 RNA aptamers on major populations of immunocompetent cells ex vivo.Comparative analysis of the antitumor effects of in situ vaccination with CpG ODNs and anti-OX40 antibodies,as well as several other combinations,such as mesyl phosphoramidate CpG ODNs and OX40 RNA aptamers,was conducted.Antibodies against programmed death 1(PD1)checkpoint inhibitors or their corresponding PD1 DNA aptamers were also added to vaccination regimens for analytical purposes.Four scenarios were considered:a weakly immunogenic Krebs-2 carcinoma grafted in CBA mice;a moderately immunogenic Lewis carcinoma grafted in C57Black/6 mice;and an immunogenic A20 B cell lymphoma or an Ehrlich carcinoma grafted in BALB/c mice.Adding anti-PD1 antibodies(CpG+αOX40+αPD1)to in situ vaccinations boosts the antitumor effect.When to be used instead of antibodies,aptamers also possess antitumor activity,although this effect was less pronounced.The strongest effect across all the tumors was observed in highly immunogenic A20 B cell lymphoma and Ehrlich carcinoma.

Primary Liver Large B-Cell Lymphoma: A Rare Diagnosis

Primary liver lymphoma is extremely rare, in most of cases it is a B cell lymphoma. Usually the diagnosis is made in middle-aged individuals and most of them have a relatively short life expectancy. In this article, the authors present a case report of a 75-year-old woman with symptoms of three weeks of evolution of diffuse abdominal pain, asthenia and anorexia. The analysis showed cyto cholestasis and the radiological image with lush hepatomegaly because of a large hepatic mass. The patient started chemotherapy and actually is well twenty months after the end of the chemotherapy.

Yinchenhao decoction attenuates obstructive jaundice-induced liver injury and hepatocyte apoptosis by suppressing protein kinase RNA-like endoplasmic reticulum kinase-induced pathway

BACKGROUND Chronic biliary obstruction results in ischemia and hypoxia of hepatocytes,and leads to apoptosis.Apoptosis is very important in regulating the homeostasis of the hepatobiliary system.Endoplasmic reticulum(ER)stress is one of the signaling pathways that induce apoptosis.Moreover,the protein kinase RNA-like endoplasmic reticulum kinase(PERK)-induced apoptotic pathway is the main way;but its role in liver injury remains unclear.Yinchenhao decoction(YCHD)is a traditional Chinese medicine formula that alleviates liver injury and apoptosis,yet its mechanism is unknown.We undertook this study to investigate the effects of YCHD on the expression of ER stress proteins and hepatocyte apoptosis in rats with obstructive jaundice(OJ).AIM To investigate whether YCHD can attenuate OJ-induced liver injury and hepatocyte apoptosis by inhibiting the PERK-CCAAT/enhancer-binding protein homologous protein(CHOP)-growth arrest and DNA damage-inducible protein 34(GADD34)pathway and B cell lymphoma/leukemia-2 related X protein(Bax)/B cell lymphoma/leukemia-2(Bcl-2)ratio.METHODS For in vivo experiments,30 rats were divided into three groups:control group,OJ model group,and YCHD-treated group.Blood was collected to detect the indicators of liver function,and liver tissues were used for histological analysis.For in vitro experiments,30 rats were divided into three groups:G1,G2,and G3.The rats in group G1 had their bile duct exposed without ligation,the rats in group G2 underwent total bile duct ligation,and the rats in group G3 were given a gavage of YCHD.According to the serum pharmacology,serum was extracted and centrifuged from the rat blood to cultivate the BRL-3A cells.Terminal deoxynucleotidyl transferase mediated dUTP nick end-labelling(TUNEL)assay was used to detect BRL-3A hepatocyte apoptosis.Alanine aminotransferase(ALT)and aspartate transaminase(AST)levels in the medium were detected.Western blot and quantitative real-time polymerase chain reaction(qRT-PCR)analyses were used to detect protein and gene expression levels of PERK,CHOP,GADD34,Bax,and Bcl-2 in the liver tissues and BRL-3A cells.RESULTS Biochemical assays and haematoxylin and eosin staining suggested severe liver function injury and liver tissue structure damage in the OJ model group.The TUNEL assay showed that massive BRL-3A rat hepatocyte apoptosis was induced by OJ.Elevated ALT and AST levels in the medium also demonstrated that hepatocytes could be destroyed by OJ.Western blot or qRT-PCR analyses showed that the protein and mRNA expression levels of PERK,CHOP,and GADD34 were significantly increased both in the rat liver tissue and BRL-3A rat hepatocytes by OJ.The Bax and Bcl-2 levels were increased,and the Bax/Bcl-2 ratio was also increased.When YCHD was used,the PERK,CHOP,GADD34,and Bax levels quickly decreased,while the Bcl-2 levels increased,and the Bax/Bcl-2 ratio decreased.CONCLUSION OJ-induced liver injury and hepatocyte apoptosis are associated with the activation of the PERK-CHOP-GADD34 pathway and increased Bax/Bcl-2 ratio.YCHD can attenuate these changes.

^(18)F-fluorodeoxyglucose PET/CT findings of a solitary primary hepatic lymphoma:A case report

Primary hepatic lymphoma is extremely rare,and only a few cases have been described on positron emission tomography(PET) or PET/computed tomography(PET/CT) imaging in the English literature.We report a case of a 55-year-old woman who presented with low-grade fever and weight loss of three months.On CT scanning,a mass was identified which appeared to be a hypoattenuating lesion,on ultrasonographic imaging,the mass was hypoechoic,therefore,liver abscess or hepatic metastasis from a gastrointestinal primary was initially suspected.Tumor markers such as alpha-fetoprotein,carcinoembryonic antigen and carbohydrate antigen 19-9 were within normal limits.PET/CT demonstrated a large abnormal ring-like hypermetabolic focus in the right liver lobe.The lesion was resected and the histo-pathological findings were consistent with lymphoma.The patient was discharged two weeks after surgery and did not receive any further treatment.After 25 mo follow-up,she is in good health.18F-fluorodeoxyglucose PET/CT is useful in confirming the diagnosis of primary hepatic lymphoma by demonstrating no other foci with high uptake in other parts of the body.

Malignant lymphoma of spleen presenting as acute pancreatitis: A case report

This is a case report of a patient who presented with acute pancreatitis without the common causes. A pancreatic biopsy revealed large B cell lymphoma. Spleen lymphoma with pancreatic involvement inducing acute pancreatitis, which is a rare disorder, was diagnosed. Here we also review the few similar cases reported in the literature.

Primary Cardiac Lymphoma: Three Case Reports and a Review of the Literature

Primary cardiac lymphoma (PCL) is a rare entity that comprises only 1% - 2% of all cardiac tumors. Due to their scarcity and variable clinical presentation, early diagnosis is challenging. In this series, three cases of PCL from a single institution are described, which highlight the spectrum of presenting features and emphasize common principles. In the first case, a 73-year-old male who presented with dyspnea was found to have a 12.1 cm mass in the right ventricle. Biopsy via cardiac catheterization revealed diffuse large B cell lymphoma (DLBCL). He was treated with chemoimmunotherapy and survived for two months. The second case describes a 55-year-old female who presented with chest pain. Imaging revealed a 3.1 cm right atrial mass and bilateral pleural effusions, with cytology from the latter demonstrating DLBCL. She was lost to follow up after three cycles of chemoimmunotherapy. In the last case, an 80-year-old female presented with weakness. A 4.0 cm mass was discovered in the right atrium and the patient expired shortly after admission. Autopsy confirmed the diagnosis of DLBCL. These case summaries are followed by a review of the clinical presentation, diagnostic approach, and treatment outcomes of PCL.

Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19 chimeric antigen receptor T therapy

Anti-CD19 chimeric antigen receptor(CAR)-T cell therapy has achieved 40%–50%long-term complete response in relapsed or refractory diffuse large B-cell lymphoma(DLBCL)patients.However,the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation.A multi-center phase I/II trial of anti-CD19 CD28z CAR-T(FKC876,ChiCTR1800019661)was conducted.Among 22 evaluable DLBCL patients,seven achieved complete remission,10 experienced partial remissions,while four had stable disease by day 29.Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients,and compared at different stages of treatment.M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells,leading to CAR-T cell therapy failure and disease progression in DLBCL.Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy,during both cell expansion and disease progression,which could not be altered by infiltrating CAR-T cells.Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments.Thus,our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

Foil-like receptor agonists induce apoptosis in mouse 3-cell lymphoma cells by altering NF-κB activation

Toll-like receptor 9 （TLR9） recognizes microbial DNA containing unmethylated cytosyl guanosyl （CpG） sequences, induces innate immune responses, and facilitates antigen-specific adaptive immunity. Recent studies report that in addition to stimulating innate immunity, TLR9 ligands induce apoptosis of TLR9 expressing cancer cells. To understand the mechanism of TLR9-induced apoptosis, we compared the effects of CpG containing oligodeoxynucleotides （CpG ODN） on a mouse B-cell lymphoma line, CH27, with those on mouse splenic B cells. CpG ODN inhibited constitutive proliferation and induced apoptosis in the CH27 B-cell lymphoma line. In contrast, CpG ODN-treated primary B cells were stimulated to proliferate and were rescued from spontaneous apoptosis. The induction of apoptosis required the ODNs to contain the CpG motif and the expression of TLR9 in lymphoma B cells. A decrease in Bcl-xl expression and an increase in Fas and Fas ligand expression accompanied lymphoma B-cell apoptosis. Treatment with the Fas ligand-neutralizing antibody inhibited CpG ODN-induced apoptosis. CpG ODN triggered a transient NF-κB activation in the B-cell lymphoma cell line, which constitutively expresses a high level of c-Myc, while CpG ODN induced sustained increases in NF-κB activation and c-Myc expression in primary B cells. Furthermore, an NF-κB inhibitor inhibited the proliferation of the CH27 B-cell lymphoma line. Our data suggest that the differential responses of lymphoma and primary B cells to CpG ODN are the result of differences in NF-KB activation. The impaired NF-KB activation in the CpG ODN-treated B-cell lymphoma cell line alters the balance between NF-κB and c-Myc, which induces Fas/Fas ligand-dependent apoptosis.

Hepatitis B virus–associated diffuse large B cell lymphoma:epidemiology,biology,clinical features and HBV reactivation

Diffuse large B cell lymphoma(DLBCL)is the most common type of lymphoma in adults with high heterogeneity.Recent studies have manifested that the occurrence and development of DLBCL is related to hepatitis B virus(HBV)infection.As a medium-to-high prevalence area of HBV infection in China,the importance and exact mechanism of HBV infection in the occurrence of DLBCL have attracted considerable attention.HBV-associated DLBCL has unique clinical characteristics,poor treatment effect and inferior prognosis.HBV reactivation caused by DLBCL treatment also needs for constant vigilance.In this review we summarize the current research progress in the epidemiology,pathogenesis,clinical characteristics,HBV reactivation and antiviral therapies of HBV-associated DLBCL,in order to provide reference for clinical diagnosis and treatment.