The role of PD-1/PD-L1 checkpoint in arsenic lung tumorigenesis

Chronic exposure to environmental arsenic promotes lung cancer. Emerging evidence indicates that compromised host immunity, particularly T cell anti-tumor immunity, may play a critical role in cancer development. However, there is a knowledge gap in terms of the effects of arsenic exposure on T cell anti-tumor immunity and how that may contribute to arsenic lung carcinogenicity. Immunosuppression has been known as a risk factor for many types of cancer, including lung cancer. The development of cancer indicates the success of immunosuppression and escape of cancer cells from host anti-tumor immunity in which T cells are the major component. The anti-tumor immunity is mainly executed by CD8 cytotoxic T cells through their anti-tumor effector function, which can be regulated by immune checkpoint pathways. Some inhibitory receptors on the T cell membrane and their ligands form these pathways, among which programmed death-1 (PD-1), a T cell inhibitory receptor, and its ligand, programmed death-ligand 1 (PD-L1), are best characterized. A/J mice are naturally sensitive to pulmonary carcinogens, prone to develop spontaneous lung tumors later in life and have been frequently used as an animal model for lung tumorigenesis research. Chronic arsenic administration through drinking water has been shown to enhance tumor formation in the lungs of A/J mice. In the current study, using this mouse model we want to determine whether PD-1/PD-L1 plays a role in arsenic-enhanced lung tumorigenesis. The results showed that prolonged arsenic exposure up-regulated PD-1/PD-L1, increased regulatory T cells (Tregs), decreased CD8/Treg ratio, inhibited T cell antitumor function in the lungs and enhanced lung tumor formation, while inhibition of PD-1/PD-L1 restored CD8/Treg ratio and T cell anti-tumor effector function, and mitigated arsenic-enhanced lung tumorigenesis. In addition, inhibition of PD-1/PD-L1 could be a potential preventive strategy to mitigate the tumorigenic action of chronic arsenic exposure.