Abstract 2602: Loss of glutathione S-Transferase omega 2 is associated with PD-L1 expression and poor prognosis in lung adenocarcinoma
Authors: Sumiya Ryusuke , Hatano Hiroto , Hagiwara Teruki , Nagasaka Satoshi , Suzuki Hiromu , Yamada Kazuhiko , Kokudo Norihiro , Kawamura Yuki I. 
Published: April 2023

Glutathione S-transferase omega 2 (GSTO2) lacks any appreciable GST activity but presents thioltransferase activity and therefore plays an important role in regulating the glutathione redox balance. In addition, GSTO2 polymorphisms are strongly associated with lung function and the risk of chronic obstructive pulmonary disease. We recently reported that GSTO2 is exclusively expressed in airway basal cells, Clara cells, and type II alveolar cells, which have self-renewal capacity in the lungs. In this study, we examined the expression of GSTO2 in non-small cell lung cancer (NSCLC) and analyzed the relationship between GSTO2 expression and clinicopathological features. We enrolled 233 patients who were diagnosed with NSCLC and underwent surgery, and immunohistochemically evaluated the expression of GSTO2 using formalin-fixed, paraffin-embedded sections of surgical specimens. While all 94 squamous cell carcinoma samples showed no GSTO2 expression, 58 of 139 lung adenocarcinoma (LAC) samples exhibited GSTO2 expression. The expression of GSTO2 in LAC samples was significantly associated with never or light (Brinkman Index &lt; 400) smoking history (P=0.0027) and histological subtypes (lepidic 85/110, 77%; acinar 30/68, 44%; papillary 18/64, 22%; micropapillary 1/6, 16.7%; solid 3/31, 9.6%; P&lt;0.0001). There were no significant differences between the groups with respect to pN, pM, EGFR mutation, ALK fusion, and ROS-1 fusion. However, GSTO2 expression in LAC significantly associated with pT1 (P&lt;0.0001), early stage (P&lt;0.0001), and absence of PD-L1 expression (P=0.0027). Moreover, patients with GSTO2-negative LAC had a significantly lower disease-free survival rate than those with GSTO2-positve LAC (P=0.028). To examine whether GSTO2 expression affects PD-L1 expression, we prepared GSTO2-transfected and mock-transfected NSCLC cell lines (A549, PC-9, and H520). However, there was no difference in PD-L1 transcription between the GSTO2 and mock transfectants. Previous studies have reported that PD-L1 protein expression is induced via the mitogen-activated protein kinase (MAPK) signaling pathways in lung cancer, glioblastoma, and hepatocellular carcinoma. Our prior finding that GSTO2 accelerates the phosphorylation of p38, a key protein of MAPK signaling (Cancer Science, 2022), suggests that GSTO2 may be involved in PD-L1 expression as a post-transcriptional regulator. In summary, our study indicates that GSTO2 loss contributes to LAC progression partially through the induction of PD-L1 expression.

Citation Format: Ryusuke Sumiya, Hiroto Hatano, Teruki Hagiwara, Satoshi Nagasaka, Hiromu Suzuki, Kazuhiko Yamada, Norihiro Kokudo, Yuki I. Kawamura. Loss of glutathione S-Transferase omega 2 is associated with PD-L1 expression and poor prognosis in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2602.