CD39: the potential target in small cell lung cancer

Abstract

Background: It has been proven that the treatment window of small cell lung cancer (SCLC) is short, so it is vital to find other possible therapeutic targets. CD39 inhibits natural killer (NK) cells and promotes the occurrence and metastasis of tumors. There has been little research about the role of CD39 in SCLC, so we explored the correlation between CD39 and other surface antigens, and its association with survival in SCLC.Methods: This study included 75 patients with SCLC from Shanghai Pulmonary Hospital. After paraffin embedding and sectioning, immunohistochemistry (IHC) was applied. Then we identify cutoff value for CD39 and other surface antigens based on the analysis of ROC curve in RFS by SPSS. All statistical analyses were based on SPSS and Graphpad Prism8. Chi-square test, Kendall's tau-b correlation analysis, Logistic regression analysis, Kaplan-Meier method, univariate and multivariate Cox regression analysis were conducted. In all analyses, P = 0.05 distinguished whether they had statistical significance. Results: Of the 75 SCLC patients enrolled in this study, 61.33% positively expressed CD39. A correlation between CD39 and programmed cell death-ligand 1 (PD-L1) (P=0.007), CD3 (P<0.001), CD4 (P<0.001), CD8 (P<0.001), and forkhead box P3 (FOXP3) (P<0.001) on tumor-infiltrating lymphocytes (TILs) was identified by correlation analysis and logistic regression analysis. Based on Kaplan-Meier survival analysis, we found that CD39 affected relapse-free survival (RFS) [negative vs. positive, 95% confidence interval (CI): 0.2765-0.9862, P=0.0390]. SCLC patients with high-expressed CD39 and low-expressed PD-L1 had poor prognosis (P<0.001). Positive expression of CD39 and negative expression of CD3, CD4, CD8, and FOXP3 also indicated shorter RFS (P=0.0409). Univariate and multivariate Cox regression analysis was performed to confirm the factors that influenced RFS. Conclusions: CD39, programmed cell death-1 (PD-1), and PD-L1 expressed on TILs but not on tumor cells. CD39 has a significant association with PD-L1, CD3, CD4, CD8, and FOXP3 on TILs. The positive expression of CD39 predicts poor prognosis. SCLC patients with low expression of CD39 combined with high expression of PD-L1 or CD3, CD4, CD8, and FOXP3 have a more favorable prognosis.

Extracellular ATP and adenosine in tumor microenvironment: Roles in epithelial–mesenchymal transition, cell migration, and invasion

“…Its expression is induced by hypoxia and tissue damage (B. Allard et al, 2017; Eltzschig et al, 2009). The increased expression of this enzyme was reported in several tumors, including ovarian cancer (Häusler et al, 2011), gastric tumor (Cai et al, 2015), hepatocellular carcinoma (Cai et al, 2016), and small cell lung cancer (Chen et al, 2020) among others. CD39 E‐NTPDase hydrolyzes ATP to ADP and to its final product AMP in the tumor milieu.…”

Immune Checkpoints OX40 and OX40L in Small-Cell Lung Cancer: Predict Prognosis and Modulate Immune Microenvironment

“…For SCLC cases, the expression profile of OX40 and OX40L and their roles in clinical outcome and tumor microenvironment (TME) remained unclear. The limited clinical benefits of immunotherapy in SCLC might as cribe to the fi nite cognition of tumor im mune microenvironment (24)(25)(26). For these reasons, we identified the OX40/OX40L protein expression and gene mutation in SCLC by immunohistochemistry (IHC) and whole-exome sequencing (WES).…”

CCL5 as a Prognostic Marker for Survival and an Indicator for Immune Checkpoint Therapies in Small Cell Lung Cancer

“…Besides CD8+ T cell, NK cells are emerging as an attractive target for immunotherapy ( 24 , 25 ). SCLC metastasis is controlled by NK cells ( 26 ).NK cells are also a potential therapeutic target for small cell lung cancer ( 27 , 28 ).…”