Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, is highly heterogeneous and invasive. Although the majority of DLBCL patients show a good response to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone treatment, approximately one-third of patients still have a poor prognosis. Many immune-targeted drugs, such as bispecific T-cell engagers and CAR T-cell therapy, have been proven effective for refractory and relapsed patients. This article reviews the progress of immune targeted therapy for DLBCL.

Epstein–Barr virus (EBV) infection is proved to be associated with clinicopathology of lymphoma. However, little is known about the relationship between EBV‐DNA status after treatment and prognosis. In this study, real‐time polymerase chain reaction (PCR) was used for quantitative detection of EBV‐DNA load in peripheral blood of all 26,527 patients with lymphoma, and the clinical characteristics and prognosis of 202 patients were retrospectively analysed, including 100 patients with positive EBV‐DNA and 102 randomly selected patients with negative EBV‐DNA. We found that the average rate of EBV‐DNA positivity in lymphomas was 0.376%, and EBV‐DNA‐positive patients presented higher risk with elevated lactate dehydrogenase (LDH) and β2‐MG level, B symptoms, secondary hemophagocytic syndrome and lower objective response rate compared to EBV‐DNA‐negative patients. Multivariate analysis revealed EBV‐DNA‐positive patients had inferior progression‐free survival (PFS) and overall survival (OS) and EBV‐DNA level before treatment was related to PFS but not OS of T/NK cell lymphoma. In T/NK cell lymphoma, EBV‐DNA converting negative after treatment was correlated with better PFS but not OS, and second‐line therapy could induce more EBV‐DNA‐negative conversion compared to CHOP‐based therapy. In all, EBV‐DNA positivity before treatment can be a biomarker representing the tumour burden and an independent prognostic factor. EBV‐DNA‐negative conversion after treatment is a good prognostic factor for T/NK cell lymphomas.

The development of acute lymphoblastic leuakemia (ALL) is partly attributed to the effects of bone marrow (BM) microenvironment, especially mesenchymal stromal cells (MSCs), which interact bilaterally with leukaemia cells, leading to ALL progression. In order to find MSCs-based microenvironment targeted therapeutic strategies, Notch1-induced T-cell ALL (T-ALL) mice models were used and dynamic alterations of BM-MSCs with increased cell viability during T-ALL development was observed. In T-ALL mice derived stroma-based condition, leukaemia cells showed significantly elevated growth capacity indicating that MSCs participated in leukaemic niche formation. RNA sequence results revealed that T-ALL derived MSCs secreted fibroblast growth factor 2 (FGF2), which combined with fibroblast growth factor receptor 2 (FGFR2) on leukaemia cells, resulting in activation of PI3K/AKT/mTOR signalling pathway in leukaemia cells. In vitro blocking the interaction between FGF2 and FGFR2 with BGJ398 (infigratinib), a FGFR1-3 kinase inhibitor, or knockdown FGF2 in MSCs by interference caused deactivation of PI3K/AKT/mTOR pathway and dysregulations of genes associated with cell cycle and apoptosis in ALL cells, leading to decrease of leukaemia cells. In mouse model received BGJ398, overall survival was extended and dissemination of leukaemia cells in BM, spleen, liver and peripheral blood was decreased. After subcutaneous injection of primary human T-ALL cells with MSCs, tumour growth was suppressed when FGF2/FGFR2 was interrupted. Thus, inhibition of FGF2/FGFR2 interaction appears to be a valid strategy to overcome BM-MSCs mediated progression of T-ALL, and BGJ398 could indeed improve outcomes in T-ALL, which provide theoretical basis of BGJ398 as a BM microenvironment based therapeutic strategy to control disease progression.

Summary Bone marrow mesenchymal stromal cells (BM‐MSCs) are implicated in the pathogenesis of acute myeloid leukaemia (AML). However, due to the high heterogeneity of AML the mechanism underlying the cross‐talk between MSCs and leukaemia cells is not well understood. We found that mixed‐lineage leukaemia‐AF9 (MLL‐AF9)‐induced AML mice‐derived MSCs had higher proliferative viability compared to wild‐type mice‐derived MSCs with ubiquitin‐conjugating enzyme E2O (Ube2o) down‐regulation. After overexpression of UBE2O in AML‐derived MSCs, the growth capacity of MSCs was reduced with nuclear factor kappa B subunit 1 (NF‐κB) pathway deactivation. In vitro co‐culture assay revealed that UBE2O‐overexpression MSCs suppressed the proliferation and promoted apoptosis of AML cells by direct contact. In vivo results revealed that the leukaemia burden was reduced and the overall survival of AML mice was prolonged, with decreased dissemination of leukaemia cells in BM, spleen, liver and peripheral blood. Additionally, subcutaneous tumorigenesis revealed that tumour growth was also suppressed in the UBE2O‐overexpression MSCs group. In conclusion, UBE2O was expressed at a low level in MLL‐AF9‐induced AML mice‐derived MSCs. Overexpression of UBE2O in MSCs suppressed their proliferation through NF‐κB pathway deactivation, which resulted in AML suppression. Our study provides a theoretical basis for a BM microenvironment‐based therapeutic strategy to control disease progression.