Updating targets for natural killer/T-cell lymphoma immunotherapy

Natural killer/T-cell lymphoma(NKTCL)is a highly invasive subtype of non-Hodgkin lymphoma,typically positive for cytoplasmic CD3,CD56,cytotoxic markers,including granzyme B and TIA1,and Epstein-Barr virus(EBV).The current treatment methods for NKTCL are associated with several drawbacks.For example,chemotherapy can lead to drug resistance,while treatment with radiotherapy alone is inadequate and results in frequent relapses.Moreover,hematopoietic stem cell transplantation exhibits limited efficacy and is not well recognized by domestic and foreign experts.In recent years,immunotherapy has shown good clinical results and has become a hot spot in cancer research.Clinical activity of targeted antibodies,such as daratumumab(anti-CD38 antibody)and brentuximab vedotin(anti-CD30 antibody),have been reported in NKTCL.Additionally,dacetuzumab and Campath-1 H have demonstrated promising results.Further encouraging data have been obtained using checkpoint inhibitors.The success of these immunotherapy agents is attributed to high expression levels of programmed death-ligand 1 in NKTCL.Furthermore,anti-CCR4 monoclonal antibodies(m Abs)exert cytotoxic actions on both CCR4+tumor cells and regulatory T cells.Depletion of these cells and the long half-life of anti-CCR4 m Abs result in enhanced induction of antitumor effector T cells.The role of IL10 in NKTCL has also been investigated.It has been proposed that exploitation of this cytokine might provide potential novel therapeutic strategies.Cellular immunotherapy with engineered cytotoxic T lymphocytes targeted against LMP1 and LMP2 has shown promising results and sustained remission.Cellular immunotherapy may be used either as maintenance therapy following initial induction chemotherapy or in cases of relapsed/refractory disease.The present review outlines the known immunotherapy targets for the treatment of NKTCL.

Inactivation of FOXO1 induces T follicular cell polarization and involves angioimmunoblastic T cell lymphoma

Objective:Angioimmunoblastic T cell lymphoma(AITL)is an aggressive form of non-Hodgkin lymphoma derived from mature T cells.However,the underlying pathogenesis of AITL remains unresolved.We aimed to explore the role of FOXO1-mediated signaling in the tumorigenesis and progression of AITL.Methods:FOXO1 expression was assessed using immunohistochemistry on a total of 46 AITL tissue samples.Retroviruses encoding FOXO1 shRNA were used to knockdown FOXO1 expression in CD4^+T cells.Flow cytometric assays analyzed the proliferation and survival of FOXO1 knockdown CD4^+T cells.Furthermore,we performed adoptive T-cell transfer experiments to identify whether inactivation of FOXO1 induced neoplastic follicular-helper T(Tfh)cell polarization and function.Results:Patients with low FOXO1 protein levels were prone to have an advanced tumor stage(P=0.049),higher ECOG ps(P=0.024),the presence of bone marrow invasion(P=0.000),and higher IPI(P=0.035).Additionally,the survival rates of patients in the FOXO1 high-expression group were significantly better than those in the FOXO1 low-expression group(χ^2=5.346,P=0.021).We also observed that inactivation of FOXO1 increased CD4^+T cell proliferation and altered the survival and cell-cycle progression of CD4^+T cells.Finally,we confirmed that inactivation of FOXO1 induces Tfh cell programing and function.Conclusions:Inactivation of FOXO1 in AITL plays a key role in the tumorigenesis and progression of AITL.We propose that FOXO1 expression could be a useful prognostic marker in AITL patients to predict poor survival,and to design appropriate therapeutic strategies.

Establishment of a Human Malignant T Lymphoma Cell Line Carrying a Retrovirus-like Particles with RT Activity

We have established an IL-2 independent malignant lymphoma line (CM-1) from peripheral T lymphocytes donated by a femalc patient with nervous systcm disease, the binlogical characteristics of CM-1 cells was studied in this paper. Another T lymphocytes,such as peripheral T lymphocytes donated by a maIe patient with multiple sclerosis, could be transformed into a malignant lymphoma line by using filtered supernatant of the CM-1 cultured medium, thus the CM-2 cell line u'as estabIished. The CM-1 and CM-2 cells were transplanted by subcutaneous inoculation into nude mice, and could cause the occurrenceof typical maIignant lymphoma. The observation of eIectron micrographs suggested the existence of virions in the CM-1 and CM-2 cells, and these virions were similar toretrovirus in the ultra-structure characteristics. lt was found that this virus possesses reverse transcriptase activity. ResuIts obtained from serological assay, molecular hybridization and PCR excluded the existence of other human viruses, which were commonly usedin our laboratory. The unknown virus possesses strong transformation activity, and probably is a new retro virus. Meanwhile, the work on the clone and sequence analysis ofthis virus are being carried out.

Intestinal NK/T cell lymphoma: A case report

BACKGROUND The incidence of intestinal NK/T cell lymphoma(NKTCL)is extremely low,and the clinical symptoms are atypical,which makes it difficult to distinguish this disorder from Crohn's disease(CD),T lymphocyte proliferative disease,and other immune disorders.The misdiagnosis rate is high,and the patient's prognosis is poor.CASE SUMMARY In this case,the patient had repeated high fever,colonoscopy revealed multiple ulcers,and the initial diagnosis was CD.The patient’s condition did not improve after treatment with hormones and infliximab,and she eventually died.Positron emission tomographic-computed tomographic and B-ultrasound were performed in our hospital and showed that multiple lymph nodes were enlarged.Immunohistochemi-stry showed that CD3 and Epstein-Barr virus encoded RNA expression was positive.Colonoscopy,tissue biopsy,and histopathology showed intestinal focal mucosal infiltration of heterotypic lymphocytes with an abnormal immune phenotype.On the basis of the patient’s medical history,auxiliary examination,and pathological findings,digestive physicians and pathologists gave the diagnosis of NKTCL.CONCLUSION Clinicians need to improve their comprehensive knowledge of NKTCL,and combination of clinical symptoms,histological characteristics,as well as colonoscopy biopsies should be considered to improve the diagnosis and thereby reduce misdiagnosis.

Muscular involvement of extranodal natural killer/T cell lymphoma misdiagnosed as polymyositis: A case report and review of literature

BACKGROUND Natural killer(NK)/T cell lymphoma is a rare and highly aggressive malignant tumor,and is a special form of non-Hodgkin's lymphoma.Although extranodal involvement is frequently found in tissues such as the skin,testicular and gastrointestinal tract etc,its presence in skeletal muscle has scarcely been reported in the literature.CASE SUMMARY We report a case of extranodal NK/T cell lymphoma with muscle swelling as the first clinical manifestation.A 42-year-old man,who initially presented with localized swelling in the double lower extremities,demonstrated gradual facial and eyelid swelling,and his imaging results showed multiple sites of muscle damage throughout the body.The final pathological results suggested NK/T cell lymphoma,and immunohistochemistry showed CD20(-),CD3(+),CD30(+),CD56(-),EBER(+),Ki67(60%),TIA-1(+)and CD68(±)staining.The muscle swelling significantly improved after treatment with chemotherapy regimens.CONCLUSION This disease is difficult to diagnose and highly invasive,and should be included in the differential diagnosis of unexplained muscle swelling.

T-CELL RECEPTOR GENE REARRANGEMENT ANALYSIS IN THE PRIMARY CUTANEOUS T-CELL LYMPHOMA

Object: The present paper is to evaluate the significance of T cell receptor (TCR) gene rearrange ments in primary cutaneous T cell lymphomas (PCTCL) as detected by analysis of Southern Blot (SBA) and polymerase chain reaction (PCR). Patients and Methods: Skin specimens and peripheral blood samples were taken from 44 patients with PCTCL, including 30 patients with mycosis fungoides (MF), 2 patients with Sezary's syndrome (SS), and 12 patients with PCTCL other than MF and SS (PNCTCL). 11 patients with a presumptive diagnosis of MF, 23 patients with lymphoproliferative dermatoses including lymphomatoid papulosis (LyP) and 8 patients with benign cutaneous lymphoid infiltrates were simultaneously studied by the amplification of junctional V (variable) J (joining) sequences of the rearranged TCRγ genes by PCR(TCRγPCR) and the analysis of TCRb chain genes by SBA(TCRβSBA) for detection of clonal gene rearrangements (GR). One lymph node specimen of a case with MF IIA was also detected by TCRγ PCR and TCRβSBA. Results: In MF, GR were detected by TCRγPCR and TCRβSBAb in 83.3 85.7% and 66.7% 71.4% of skin specimens of cases IIA IIB and in 57.1% 70.0% and 14.3% 10.0% of those of cases IA IB, respectively. GR were seen in 66.7% 71.4% and 33.3% 43.0.% of blood samples of cases IIA IIB, and 42.9% 40.0% and 0 10.0% of those of cases IA IB, respectively. GR was confirmed by TCRγ PCR and TCRβSBA in one lymph node showing dermato pathic lymphadenopathy of a case with MF IIA. In 11 patients of clinically suspected MF, GR were present in skin specimens of 5 cases (45.4%) and in blood samples of 3 cases ( 27.3% ) by TCRγ PCR. In PNCTCL, GR were found in 9 skin specimens (90.0%) from 10 patients detected by TCRγ PCR and in 6 skin specimens (75.0%) from 8 patients detected by TCRβSBA. GR were also seen in 6 blood samples (72.8%) from 11 patients detected by TCRγ PCR, and in 7 blood samples (70.0%) from 10 patients by TCRβSBA. In SS and LyP, GR were detected by TCRγ PCR and TCRβSBA in each of the two skin specimens of two cases with LyP and in each of the two blood samples of two cases with SS. GR were seen in one skin specimen of one case with SS and one blood sample of one case with LyP detected by TCRγPCR. Conclusions: This study demonstrated that TCRγ PCR is a rapid, more sensitive tool than TCRβSBA, can be used in the analysis of T cell clonality in skin, lymph node and blood samples of patients with PCTCL and indicated that this method forms a useful supplement to other methods for diagnosis of early and suspected MF, confirmation of PNCTCL and determination of extracutaneous involvement of lymph node and blood.

THE DETECTION OF CD56 AND EPSTEIN-BARR VIRUS IN T-CELL LYMPHOMAS

Objective: To study the relationship between EBV infection and the expression of CD56 in T cell lymphomas (TCLs). Methods: 46 cases of TCLs and 15 cases of reactive hyperplasia of lymphonodes (RHs) were detected CD56 by immunohistochemistry and EBERs by in situ hybridization. Results: 8 cases of 46 TCLs (17.4%) showed CD56 positive. On sites, CD56 positive rate of nasopharyngeal TCLs was highest (5/17, 29.4%), and on subtypes, that of DLs was highest (6/16, 37.5%). Additionally, 4 RHs were also CD56 positive. Of 46 TCLs, 24 showed expression of EBERs. There were only 4 TCLs expressing both CD56 and EBERs. Conclusion: The expression of CD56 was not especially for TCLs that EBV infected. EBV infection was not related with CD56 positive TCLs. The findings also suggested the expression of CD56 in TCLs be possibly related to original sites and subtypes of TCLs.

NUCLEOLAR ORGANIZER REGIONS IN CUTANEOUS T CELL LYMPHOMAS

The present work studied the application of AgNOR count to differential diagnosis between cutaneous T cell lymphoma (CTCL) and cutaneous pseudolymphoma (CPL). Paraffin sections from 50 mycosis fungoides (22 MFI-Premycotic stage, 24 MF Ⅰ infiltrative stage and 4 MF Ⅲ - tumor stage), 2 nonepidermotropic cutaneous T cell lymphoma (NECTCL) and 9 CPL were investigated. In each case, 200 cells randomly selected were examined using a × 100 oil immersion lens. The mean number, standard deviation and standard error of the mean of AgNOR counts were as follows: MFⅠ 1.17±0.09, SEM = 0.01; MⅡ 1.17±0.01, SEM = 0.01; MF Ⅲ. 3.55±0.87, SEM = 0.43; NECTCL 4.5±0.28, SEM -0.199; CPL 1.17±0.1, SEM ± 0.03. The results revealed a highly significant difference between CTCL (MFⅢ+NECTCL) and CPL (t = 4.75, P<0.001), tumor stage (MF Ⅲ) and pretumor stage (MFI, MF Ⅱ) of mycosis fungoides (t = 4.75, P<0.001). Thus. AgNOR count is valuable in differential diagnosis.

The significance and features of apoptosis and proliferation of NK/T cell lymphoma

Objective:The aim was to study the features and clinical significance of cell apoptosis and proliferation of NK/T cell lymphoma.Methods:TdT-mediated dUTP nick end labeling and immunohistochemical Streptavidin-peroxidase method were used to study cell apoptosis and the expression of proliferation cell nuclear antigen in 25 NK/T cell lymphoma and 10 reactive lymphoid tissues.Results:Apoptotic index(AI) and proliferative index(PI) averaged(1.92%±0.86%) and(41.48%±5.10%) respectively in the 25 NK/T cell lymphomas and(6.70%±1.89%) and(20.10%±2.77%) in the 10 reactive lymphoid tissues.Compared with reactive lymphoid tissues,AI was significantly reduced in NK/T cell lymphoma(t=10.80,P<0.01) while PI significantly increased(t=12.39,P<0.01).In addition,in NK/T cell lymphoma,AI and PI were positively related(r=0.69,P<0.01).Conclusion:In NK/T cell lymphoma,cell apoptosis is reduced while cell proliferation increased.The imbalance between cell apoptosis and cell proliferation is closely related to the development and progression of NK/T cell lymphoma.

Multiple cerebral lesions in a patient with refractory celiac disease:A case report

BACKGROUND Enteropathy-associated T cell lymphoma(EATL)is an aggressive intestinal T cell lymphoma derived from intraepithelial lymphocytes,which occurs in individuals with celiac disease(CD).Cerebral involvement is an extremely rare condition and as described so far,lymphoma lesions may present as parenchymal predominantly supratentorial or leptomeningeal involvement.We describe a case of EATL with multifocal supra-and infratentorial brain involvement in a patient with refractory celiac disease(RCD).CASE SUMMARY A 58-years old man with known CD developed ulcerative jejunitis and was diagnosed with RCD type II.Six months later he presented with subacute cerebellar symptoms(gait ataxia,double vision,dizziness).Cranial magnetic resonance imaging(MRI)revealed multifocal T2 hyperintense supra-and infratentorial lesions.Laboratory studies of blood and cerebrospinal fluid were inconspicuous for infectious,inflammatory or autoimmune diseases.18Ffluorodeoxyglucose-positron emission tomography/computed tomography(18FDG-PET/CT)scan showed a suspect hypermetabolic lesion in the left upper abdomen and consequent surgical jejunal resection revealed the diagnosis of EATL.During the diagnostic work-up,neurological symptoms aggravated and evolved refractory to high-dosage cortisone.Recurrent MRI scans showed progressive cerebral lesions,highly suspicious for lymphoma and methotrexate chemotherapy was initiated.Unfortunately,clinically the patient responded only transiently.Finally,cerebral biopsy confirmed the diagnosis of cerebral involvement of EATL.Considering the poor prognosis and deterioration of the performance status,best supportive care was started.The patient passed away three weeks after diagnosis.CONCLUSION EATL with cerebral involvement must be considered as a possible differential diagnosis in patients with known RCD presenting with neurological symptoms.

Re:Association between intestinal neoplasms and celiac disease-beyond celiac disease and more

The association between celiac disease and enteropathy-associated T cell lymphoma has been known.The pathogenesis of the development of malignant neoplasms remains limited.In addition to celiac disease,we believe that other underlying mechanisms contribute to the developing malignant neoplasms.

Aberrant expression of CD56 by circulating Sézary syndrome malignant T lymphocytes

Sézary syndrome(SS) is an aggressive variant of cutaneous T cell lymphoma characterized by the presence of malignant T cells in the skin, peripheral blood and lymph nodes. The tumoral population typically displays a CD3+ CD4+ CD45RO+ memory T cell phenotype. We report a case of SS with an aberrant CD56+ immunophenotype. This patient presented with a generalized erythroderma and palpable small axillary lymph nodes.SS(stage IVA) was diagnosed on histological criteria and by the detection of a major T cell clone in skin and blood, an elevated CD4/CD8 T cell ratio and Sézary cells count > 1000/mm3. Beside the Sézary cell marker KIR3DL2, immunostainings revealed that two third of the malignant cells expressed CD56 but no other natural killer(NK) cell marker such as CD16, CD160 or NKp46. This atypical expression was not linked to an activation-dependent process and remained stable during the time course of the disease. No loss of the panT-cell markers CD2, CD3 or CD4 was detected while a complete down-modulation of CD26 was observed. Despite several lines of treatment, no durable amelioration was observed and patient died after 10 mo of follow-up. Because this CD4+ CD56+ SS case is the only one reported so far, the functional significance of CD56 expression remained difficult to assess in terms of aggressiveness and prognosis.

Cutaneous Manifestations and Treatment Advances of Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma(ATLL)is an aggressive peripheral T-cell lymphoma caused by the human T lymphotropic virus type-1.The skin is affected in approximately half of ATLL patients,and skin lesions may be the first manifestation of the disease.The skin lesions of ATLL are polymorphous,and depend on the type of skin eruption,which makes it possible for doctors to predict the prognosis of the disease based on the characteristics of skin lesions.In this review article,we describe the clinical manifestations and histopathological patterns of skin lesions in ATLL,focus on its diagnostic and prognostic significance,and also summarize the advances in the treatment of ATLL.

Comparison of allogeneic or autologous hematopoietic stem cell transplant for high-risk peripheral T cell lymphomas

Objective To evaluate the efficacy of auto-HSCT and allo-HSCT in the treatment of high risk peripheral T cell lymphoma(PTCL).Methods From July 2007 to July 2014,60 cases of high risk PTCL were analyzed retrospectively.Results All 60 patients were at high risk group(carried with IPI≥3),with a median age of

Clinicopathologic,immunophenotypic and ultrastructrual analyses of ATLL patients with cutaneous involvement

Objective To study 4 cases of adult T cell leukemia/lymphoma (ATLL) as sociated with cutaneous lesions for clinicopathology, immunophenotype, human T cell leukemia/lymphoma virus type Ⅰ (HTLV Ⅰ) provirus DNA and their ultrastru cture. At the same time, HTLV Ⅰ provirus DNA of ATLL patients were also compar ed with 18 cases of cutaneous lymphoma (CL), two cases of actinic reticuloid as well as two cases of lymphocytic infiltration.Methods Immunohistochemistry studies were carried out on the infiltrati ng cells using monoclonal antibodies against CD45 RO, CD20, CD68 on paraffin e mbedded sections by ABC method and using monoclonal antibodies against CD3, CD4 and CD8 with indirect immunofluorescence (IIF) on frozen sections. Skin biopsies were examined by electron microscope. Serum and bone marrow cells were tested f or antibodies against HTLV Ⅰ associated antigen by IIF, and HTLV Ⅰ provirus DNA was examined by PCR method.Results The research showed four patients with ATLL manifesting cutaneo u s lesions, were subsequently found with additional systemic symptoms, as extensi vely enlarged superficial lymph node, abnormal increased IL 2 receptor, flower like cells in their peripheral blood and marrow. The HTLV Ⅰ provirus DNA was positi ve in the peripheral blood, bone marrow, cutaneous lesions and lymph node biopsy specimens by using PCR amplification of specific HTLV Ⅰ fragment while 18 cas es of the CL were negative for HTLV Ⅰ. The special ultrastructure of skin lesi ons was also found in ATLL patients.Conclusions The cutaneous involvement in ATLL is a type of cutaneous T cell lymphoma (CTCL) but shows some differential immunological markers for diffe rential diagnosis. The examination of HTLV Ⅰ antibodies or HTLV Ⅰ provirus D NA is necessary for diagnosis of ATLL. The ultrastrustural characteristics in skin lesions of ATLL were of atypic al lymphocytes and mononuclear cells invading the epidermis, and the mononuclear cells are possessing the phagocytic function and phagocytizing the degenerated epidermic cells or lymphocytes.