Over-expression of PD-L1 in cancer cells leads to Dysregulation of Treg/Th17 cell ratio

Considering the increased expression of PD-L1 in cancer cells, in the tumor microenvironment, numerous studies have reported increased expression of its receptor, PD1, in T lymphocytes (Chemnitz et al., 2004; Dorfman et al., 2006; Simon and Labarriere, 2017). PD-L1 influences Treg and Th17 differentiation through binding to PD1: it downregulates Akt, mTOR, and ERK2 during Treg differentiation (Francisco et al., 2009) while activating STAT1 and inhibiting STAT3 in Th17 cells (Zhang et al., 2017). Consequently, a higher expression of PD-L1, particularly in cancer cells, leads to a decrease in both the number and activity of Th17 cells, as well as an increased activity of Treg cells (Francisco et al., 2009; Ohaegbulam et al., 2015), which are known to suppress the immune response and promote tolerance.

Other studies have used inhibitory mechanisms to examine Treg function, and to date, two main therapeutic strategies are based on these pathways: CTLA-4 and PD1/PD-L1 blockade. The CTLA-4 pathway acts in the early stages of immune activation to limit T cell proliferation, unlike the PD1/PD-L1 pathway, modulating later the lymphocytes that are already involved in the response. Simpson et al. in 2013 used CTLA-4 KO mice and showed a depletion of Treg in the TME (Simpson et al., 2013); in another study, patients received an anti-CTLA-4, an anti-PD-L1, or both therapies. The authors found that the anti-CTLA-4 therapy improves Th17 expansion. On the other hand, Li et al. (2022) presented several PD1 inhibitors (such as Nivolumab, Pembrolizumab, and Camrelizumab), as well as monoclonal antibodies against PD-L1 (such as Atezolizumab and Durvalumab) (Li et al., 2022): these drugs reduce the activation of the PD1/PD-L1 axis, thereby reducing the population of Treg cells; this restores a more balanced ratio between Tregs and Th17 cells, which consequently enhances tumor immunosensitivity.