Tumor Immune Microenvironment Components and Checkpoint Molecules in Anaplastic Variant of Diffuse Large B-Cell Lymphoma

Abstract

BackgroundAnaplastic diffuse large B-cell lymphoma(A-DLBCL) is a rare morphological subtype characterized by the presence of polygonal, bizarre-shaped tumor cells. Our previous research found that A-DLBCL displays many genetic alterations and biological features that differ greatly from those of ordinary DLBCL. However, the status of tumor immune microenvironment components and checkpoint molecules in A-DLBCL remains unclear.MethodsThirty A-DLBCL patients were enrolled to study tumor immune microenvironment components and checkpoint molecules and their associations with clinicopathological features and prognosis.ResultsPatients with A-DLBCL presented higher expression of PD-L1 (40% vs 10%, P=0.004) than patients with ordinary DLBCL. FISH analysis showed that extra copies of PD-L1 were more frequent in A-DLBCL cases than in ordinary DLBCL cases (23.3% vs 4.0%, P=0.001). The numbers of PD-1+ TILs (tumor infiltrating lymphocytes) and CD8+T cells were significantly lower in A-DLBCL versus ordinary DLBCL. In contrast, the numbers of GATA3+ Th2 cells, FOXP3+ Tregs and CD33+ myeloid-derived suppressor cells (MDSCs) were significantly higher in A-DLBCL than in ordinary DLBCL. The associations between clinicopathological features and tumor immune microenvironment cell frequency were analyzed in A-DLBCL patients. Briefly, the number of PD-1+ TILs was lower and the number of CD33+ MDSCs was higher in patients with mutated TP53 compared to those with wild-type TP53. The number of FOXP3+ Tregs was much lower in patients with a noncomplete response (CR) to chemotherapy than in those with a complete response. The number of CD8+ T cells showed a decreasing trend in patients with high International Prognostic Index (IPI) scores and in those with concurrent MYC and BCL2 and/or BCL6 abnormalities. Univariate survival analysis showed that patients with PD-L1+, mPD-L1+(PD-L1+ nonmalignant stromal cells) or mPD-L1+ status had a significantly poorer overall survival (OS) than those with PD-L1- status. An increase in the number of CD3+ T cells, FOXP3+ Treg cells and T-bet+ Th1 cells was significantly associated with prolonged OS in patients with A-DLBCL.ConclusionOur study suggests that A-DLBCL displays a distinct pattern of tumor immune microenvironment components and checkpoint molecules that distinguish it from ordinary DLBCL. The analysis of tumor immune microenvironment components and checkpoint molecules could help in predicting the prognosis of A-DLBCL patients and determining therapeutic strategies targeting the tumor immune microenvironment.

Prognostic value of FOXP3+ regulatory T cells in patients with diffuse large B-cell lymphoma: a systematic review and meta-analysis

“…Ultimately, 14 studies including 1501 patients were included in our meta-analysis. The key characteristics of the 14 studies8 10–12 15 23–31 are presented in table 1.…”

“…Among the 14 studies, 138 10–12 15 23–27 29–31 included the HR with 95% CI for OS, 5 studies 10 11 15 24 30 reported the HR and 95% CI for PFS, 1 study10 provided the HR and 95% CI for EFS, and 1 study28 reported the HR and 95% CI for DSS. The HRs and the related 95% CIs in four articles10 15 25 26 were based on multivariable analysis models.…”

“…Nine studies8 10 15 23 25–27 30 31 were of high quality based on the NOS score of ≥6. In total, we found that five studies11 12 24 28 29 achieved a score of 5, four8 27 30 31 achieved a score of 6, four10 15 23 25 achieved a score of 7, and one26 achieved a score of 8.…”

Special clinicopathological features of anaplastic diffuse large B-cell lymphoma: a case report and literature review

“…10 Moreover, its positive signal was always located in the tumor cell membrane, unlike the classic ALCL, it is more located in the tumor cell membrane and Golgi region. 19 In 2001, New Zealand scholars proposed that the expression of CD30 in A-DLBCL may be related to its anaplastic features and survival rate. 20 In previous studies, it is still controversial about whether CD30 is related to the prognosis of patients.…”

Impact of Qi-Invigorating Traditional Chinese Medicines on Diffuse Large B Cell Lymphoma Based on Network Pharmacology and Experimental Validation

“…Therefore, to explore the mechanisms of Qi-invigorating herbs for DLBCL treatment in depth, we conduct a comprehensive TME analysis for hub genes. In DLBCL microenvironment, although much is still unknown concerning the composition of immune cells, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, myeloid DCs and MDSCs have been widely tested as independent predictors of DLBCL outcome ( Azzaoui et al, 2016 ; Chen et al, 2016 ; Judd et al, 2017 ; Kusano et al, 2017 ; Ciavarella et al, 2018 ; Staiger et al, 2020 ; Merdan et al, 2021 ; Xu et al, 2021 ). Manfroi et al ( Manfroi et al, 2017 ) further demonstrated an association between neutrophils and A Proliferation-Inducing TNF Ligand (APRIL).…”