Na, K-ATPase α1 cooperates with its endogenous ligand to reprogram immune microenvironment of lung carcinoma and promotes immune escape

Dysregulated endocrine hormones (EHs) contribute to tumorigenesis, but how EHs affect the tumor immune microenvironment (TIM) and the immunotherapy of non-small cell lung cancer (NSCLC) is still unclear. Here, endogenous ouabain (EO), an adrenergic hormone, is elevated in patients with NSCLC and closely related to tumor pathological stage, metastasis, and survival. EO promotes the suppression of TIM in vivo by modulating the expression of immune checkpoint proteins, in which programmed cell death protein ligand 1 (PD-L1) plays a major role. EO increases PD-L1 transcription; however, the EO receptor Na-and K-dependent adenosine triphos-phatase (Na, K-ATPase) alpha 1 interacts with PD-L1 to trigger the endocytic degradation of PD-L1. This seemingly contradictory result led us to discover the mechanism whereby EO cooperates with Na, K-ATPase alpha 1 to finely control PD-L1 expression and dampen tumoral immunity. In conclusion, the Na, K-ATPase alpha 1/EO signaling fa-cilitates immune escape in lung cancer, and manipulation of this signaling shows great promise in improving immunotherapy for lung adenocarcinoma.

Automated summary

Endogenous ouabain (EO) is elevated in patients with NSCLC and closely related to tumor stage, metastasis, and survival. EO promotes TIM suppression in vivo by modulating the expression of immune checkpoint proteins, particularly PD-L1. EO increases PD-L1 transcription, but its receptor Na, K-ATPase alpha 1 interacts with PD-L1 to induce its endocytic degradation, finely controlling PD-L1 expression and dampening tumoral immunity.