Glucose-6-phosphate dehydrogenase correlates with tumor immune activity and programmed death ligand-1 expression in Merkel cell carcinoma

Abstract

BackgroundMerkel cell carcinoma (MCC) is a rare and highly malignant skin cancer. Some cases have a good prognosis and spontaneous regression can occur. Reported prognostic markers, such as Merkel cell polyoma virus infection or programmed death ligand-1 (PD-L1) expression, remain insufficient for precisely estimating the vastly different patient outcomes. We performed RNA sequencing to evaluate the immune response and comprehensively estimate prognostic values of immunogenic factors in patients with MCC.MethodsWe collected 90 specimens from 71 patients and 53 blood serum samples from 21 patients with MCC at 10 facilities. The mRNA was extracted from formalin-fixed paraffin-embedded tissues. Next-generation sequencing, immunohistochemical staining and blood serum tests were performed.ResultsNext-generation sequencing results classified MCC samples into two types: the ‘immune active type’ was associated with better clinical outcomes than the ‘cell division type’. Expression of the glucose-6-phosphate dehydrogenase (G6PD) gene was highly significantly upregulated in the ‘cell division type’. Among 395 genes, G6PD expression correlated with the presence of lymph node or distant metastases during the disease course and significantly negatively correlated with PD-L1 expression. Immunohistochemical staining of G6PD also correlated with disease-specific survival and exhibited less heterogeneity compared with PD-L1 expression. G6PD activity could be measured by a blood serum test. The detection values significantly increased as the cancer stage progressed and significantly decreased after treatment.ConclusionsG6PD expression was an immunohistochemically and serum-detectable prognostic marker that negatively correlated with immune activity and PD-L1 levels, and could be used to predict the immunotherapy response.

Uncovering N4-Acetylcytidine-Related mRNA Modification Pattern and Landscape of Stemness and Immunity in Hepatocellular Carcinoma

“…In addition, the G6PD-NADPH redox system was shown to be important for stabilizing the metabolism of T cells and regulating antitumor immunity ( Gu et al, 2021 ). It was reported as a prognostic marker to predict the immunotherapy response of Merkel cell carcinoma ( Nakamura et al, 2020 ). For tumor protein p53 inducible protein 3 ( TP53I3 ), it functions as reactive oxygen species and involves in DNA damage response pathway ( Kotsinas et al, 2012 ).…”

Tertiary Lymphoid Structures and Chemokine Landscape in Virus-Positive and Virus-Negative Merkel Cell Carcinoma

“…For example, based on the RNA sequencing results, G6PD was significantly upregulated in MCPyV-negative/TLS-negative samples. Glucose-6-phosphate dehydrogenase (G6PD) is a factor that we previously reported as a promising prognostic and immune activity biomarker in MCC ( 15 ). Thus, in the present study using the same cohort, G6PD was highly expressed, indicating a poor prognosis as well as low immune activity in this group.…”

Tumor Glucose and Fatty Acid Metabolism in the Context of Anthracycline and Taxane-Based (Neo)Adjuvant Chemotherapy in Breast Carcinomas

“…The first step of the pentose phosphate pathway (PPP) is catalyzed by the G6PD enzyme. A relatively high number of studies have interrogated the role of G6PD in different cancer types but how the overexpression of G6PD contributes to the development of different tumors is largely unknown ( 82 ). Yang HC et al in a very recent study have demonstrated that deregulated G6PD status and oxidative stress are highly related and are involved in cancer progression ( 83 ).…”