title: CD4+Foxp3-IL-10+Tr1 Cells Promote Relapse of Diffuse Large B Cell Lymphoma by Enhancing the Survival of Malignant B Cells and Suppressing Antitumor T Cell Immunity.
abstract: Diffuse large B cell lymphoma (DLBCL) is a common B cell malignancy. Complete remission can be achieved in most patients by conventional treatment with rituximab and chemotherapy. However, a subset of remission individuals will develop a relapsed disease for obscure reasons. CD4+Foxp3-IL-10+cell (Tr1) is a novel cell subtype with the capacity to suppress pro-inflammatory responses, but has not been extensively studied in most tumors. In this study, we investigated the potential role of Tr1 cells in DLBCL. We found that compared to that in healthy controls, the frequency of Tr1 cells was significantly increased in DLBCL patients, even during complete remission. Further study showed that these Tr1 cells were enriched in the CD25low/-Foxp3-CD49b+LAG-3+fraction and could be developed in vitro from naive CD45RA+CD4+T cells. To examine the effect of Tr1 upregulation, we cocultured the enriched in vitro-induced Tr1 cells (iTr1) with autologous primary DLBCL cells and CD3+T cells and found that iTr1 cells both enhanced the survival of CD20+DLBCL tumor cells and suppressed the antitumor response of CD3+T cells through the production of IL-10. Furthermore, the frequency of CD4+Foxp3-IL-10+Tr1 cells in DLBCL patients during complete remission is directly associated with the risk of relapse. Together, these results suggested that Tr1 cells contributed to tumor cell maintenance and may serve as a prognostic marker and therapeutic target.
authors.affiliation: Department of Hematology, Liaocheng People's Hospital , Liaocheng, China .
authors.forename: Guozhen
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Hematology, Liaocheng People's Hospital , Liaocheng, China .
authors.forename: Jing
authors.initials: J
authors.lastname: Luan
authors.affiliation: Department of Hematology, Liaocheng People's Hospital , Liaocheng, China .
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D002470:Cell Survival; D018920:Coculture Techniques; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D039421:Integrin alpha2 / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis* / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use; D061251:Primary Cell Culture; D011379:Prognosis; D012008:Recurrence; D012074:Remission Induction; D000069283:Rituximab; D014750:Vincristine / Q000627:therapeutic use; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; D039421:Integrin alpha2; C571759:R-CHOP protocol; D016753:Interleukin-10; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human
keywords: DLBCL; Tr1 cell