The Warburg effect and tumour immune microenvironment in extramammary Paget's disease: overexpression of lactate dehydrogenase A correlates with immune resistance

Background Extramammary Paget's disease (EMPD) is a rare malignant skin cancer. One of the hallmarks of cancers, including EMPD, is an enhancement of aerobic glycolysis, which is also known as the Warburg effect. In the last step of glycolysis, the enzyme lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactic acid, the accumulation of which contributes to the creation of an acidic tumour microenvironment. This in turn results in immunosuppression in various types of cancers. However, the contribution of these pathways has not been well‐studied in EMPD. Objective To investigate the significance of the Warburg effect and its contribution to the tumour immune microenvironment in EMPD. Methods The mRNA expression levels of molecules involved in glycolysis and immune‐related cytokines were examined by ddPCR. The number of immune cells was assessed by immunohistochemistry (IHC). Results The levels of two glycolytic enzymes, HK2 and LDHA, in tumour tissues were significantly increased compared to those in paired‐normal tissues. IHC analyses revealed increased numbers of PD‐L1+, PD‐1+, CD163+ M2 macrophages, Iba1+ macrophages and Foxp3+ Tregs that were associated with high LDHA levels in EMPD. ddPCR demonstrated that multiple cytokines including IL‐4, IL‐6, IL‐10, TGF‐β and CCL‐2 were upregulated and associated with high LDHA levels in EMPD. Statistical analyses showed that IL‐6 mRNA expression correlated with the number of CD163+, Iba‐1+ and Foxp3+ cells. Conclusion The Warburg effect contributes to immunomodulation in the tumour microenvironment and further elucidation may lead to better understanding of the pathogenesis of EMPD.