Novel immune checkpoint blockades, including those targeting CD73 and A2aR, are being evaluated in malignancies in clinical trials. Here, we investigated the expression of CD73 and A2aR as well as tumor‐infiltrating lymphocytes (TILs), and analyzed their correlations with clinicopathological characteristics and survival in diffuse large B‐cell lymphoma (DLBCL). We found that CD73 expression on tumor cells, rather than the total protein and gene levels of CD73, was associated with survival. Patients with CD73+/Pax‐5+ (median survival, 57.8 months; 95% CI, 46.4–69.3) experienced significantly poorer outcomes than those with CD73−/Pax‐5+ (median survival, 73.5 months; 95% CI, 65.9–81.2). Additionally, A2aR expression on both total TILs and CD8+ TILs was correlated with survival. Patients with A2aR+ TILs (median survival, 53.3 months; 95% CI, 40.6–66.0) had a significantly shorter survival time than patients with A2aR− TILs (median survival, 74.5 months; 95% CI, 67.5–81.5). Spearman's rank test showed that CD73 expression on tumor cells was positively correlated with A2aR expression on TILs (R = 0.395, p = 0.001). We further found that patients could be more precisely stratified through the combination of CD73 tumor cell expression and A2aR TILs expression, and patients with CD73+/Pax‐5+ and A2aR+ TILs experienced the worst outcome. We also revealed that patients with CD73+/Pax‐5+ and low CD8+ TILs or low absolute lymphocyte counts had unfavorable outcomes. Overall, our findings uncovered that patients with CD73+ on tumor cells as well as A2aR+ on TILs or low CD8+ TILs exhibited inferior survival, supporting potential combination strategies using CD73/A2aR immunosuppressive blockades as treatment options for DLBCL patients.

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Epigenetics serve a key role in peripheral T cell lymphoma (PTCL). The purpose of the present study was to investigate the clinical significance of enhancer of zeste homolog 2 (EZH2) and histone deacetylase 1 and 2 (HDAC1/2) expression in PTCL. A total of 82 patients were enrolled in the present study, including 43 with PTCL not otherwise specified (PTCL-NOS), 10 with angioimmunoblastic T-cell lymphoma (AITL), 14 with natural killer/T-cell lymphoma (NK/TCL) and 15 with anaplastic large cell lymphoma (ALCL). EZH2 and HDAC1/2 expression was detected by immunohistochemistry and any correlations between them were evaluated. Additionally, any correlations between EZH2 or HDAC1/2 expression and a number of clinicopathological characteristics were analyzed, and survival curves were created. Results revealed that 55.8% of patients with PTCL-NOS, 57.1% of patients with NK/TCL, 86.7% of patients ALCL and 50% of patients with AITL highly expressed HDAC1. Furthermore, 58.1% of patients with PTCL-NOS, 57.1% of patients with NK/TCL, 53.3% of patients with ALCL and 60% of patients with AITL highly expressed HDAC2. Additionally, 67.5% of patients with PTCL-NOS, 50% of patients with NK/TCL, 73.3% of patients with ALCL and 60% of patients with AITL highly expressed EZH2. EZH2 expression was significantly correlated with the presence of B symptoms, elevated LDH and elevated β2 microglobulin (B2M; P<0.05), and HDAC2 expression was significantly correlated with sex, advanced clinical stages, high international prognostic index scores and elevated B2M levels (P<0.05) in all the patients with PTCL. However, different subtypes of PTCL are correlated with different clinical characteristics. Patients with PTCL highly expressing EZH2 or HDAC2 exhibit a poorer overall survival rate. In conclusion, EZH2 and HDAC1/2 were frequently upregulated in patients with PTCL, and the patients with a higher EZH2 and HDAC2 expression usually exhibited a poorer survival rate. Therefore, EZH2 and HDAC2 may be prognostic markers in patients with PTCL, particularly in those with PTCL-NOS.

Immune checkpoints, including PD‐1/PD‐L1, play an important role in immunosuppression in various malignancies. Elevated levels of soluble programmed death ligand 1 (sPD‐L1) are associated with worse prognosis in multiple myeloma and diffuse large B cell lymphoma. Herein, the purpose of this study is to investigate the relationships between plasma sPD‐L1 levels and clinical response in peripheral T‐cell lymphoma (PTCL) patients. A total of 37 PTCL patients and 20 healthy volunteers were enrolled. Peripheral blood from patients was collected prior to systemic therapy. Plasma levels of sPD‐L1 and IFN‐γ were measured by enzyme‐linked immunosorbent assay (ELISA). PD‐L1 expression in tissues was detected by immunohistochemistry (IHC). Clinical response for patients was evaluated. ONCOMINE database analyses showed that PD‐L1 mRNA expression was significantly upregulated in PTCLs. The median sPD‐L1 level was 0.729 ng/mL for 20 healthy volunteers and 1.696 ng/mL for 37 PTCL patients which was significantly higher than that in healthy volunteers (0.000). The sPD‐L1 level was positively correlated with IFN‐γ level (0.000, r = 0.849) and was also positively associated with clinical staging (0.045), LDH level (0.003), and β2‐MG level (0.045). Patients with high sPD‐L1 level had lower overall response rate than those with low sPD‐L1 level (88.9% vs 50.0%, 0.022) and tended to have poorer PFS and OS. PD‐L1 expression in tissues matched very well with the sPD‐L1 level in PTCL patients. In conclusion, PTCL patients had higher sPD‐L1 level compared with healthy volunteers. High sPD‐L1 level was correlated with worse clinical response, suggesting that sPD‐L1 level was an underlying plasma biomarker to predict the prognosis for PTCL patients.

In the process of enlarging of tumors, the dissolving tissue structures and remodeling endothelial cells for restoring gas exchange and nutritional support, further facilitate tumor cell invasion and metastasis. Activation of Ras plays a critical role in the development of esophageal squamous cell carcinoma (ESCC), but the underlying mechanisms remain poorly understood. We therefore investigated whether Ras guanyl-releasing protein 3 (RasGRP3), a Ras activator, could promote metastasis by inducing vascular regeneration and further epithelial-mesenchymal transition under nutrient stress (NS). In the present study, we explored that the accumulation of RasGRP3 regulated vascular endothelial growth factor-A production, co-stimulated Notch pathway with high expression of Notch intracellular domain (NICD) and Hes1. Moreover, ESCC cells under NS increased the expression of vimentin, Snail, Slug and MMP9 proteins; while inhibition of Notch activation by DAPT (a γ-secretase inhibitor) or RasGRP3-targeted RNA interference prevented from the effect. In conclusion, these findings provide a new insight into the upregulation of RasGRP3 involved in Notch pathway activation in the development of ESCC, especially under nutrient deprivation.