Caught in the middle: MARCH5 mediates PD-1-induced IL-2R degradation

Blockade of the PD-L1/PD-1 pathway in combination of IL-2 therapy appears to yield synergistic anti-tumor immunity in the treatment of various cancers.In a recent paper published in Cell Research, Liu et al. uncover previously unknown synergistic mechanisms and identify FDA-approved pitavastatin as a potential drug to facilitate such synergy.The tumor microenvironment (TME) is a complex, heterogeneous structure which hosts tumor-immune cell interactions.][3] This interaction mediates CD8 + T cell dysfunction in the TME, and antibodies targeting the PD-L1/PD-1 pathway have boosted antitumor immunity and provided long-term remission for a fraction of patients with a variety of tumors. 1,4Despite this, most patients do not respond to therapy, for reasons still poorly understood, prompting the consideration of combination therapy. 4,5ne proposed combination includes the use of IL-2. 6-8Unfortunately, IL-2 requires high doses that lead to serious toxicities. 6However, combination therapy with PD-L1/PD-1 blockade allows for low doses of IL-2. 9 Recently, PD-L1/PD-1 blockade in combination with IL-2 has shown initial promise in animal models [6][7][8] and is now in clinical trials. 10The mechanisms underlying this may be related to upregulation of IL-2Rα c (CD25). 10 However, it is unknown whether PD-L1/PD-1 blockade regulates IL-2R level.New data in a recent paper of Cell Research from Liu et al. reveal that PD-1 signaling regulates IL-2Rγ c (CD132) level via induction of MARCH5, an E3 ubiquitin ligase that targets γ c for lysosomal degradation. 11They also find that γ c can be inactivated through SHP2 dephosphorylation induced by PD-1 signaling.Overall, these data uncover new mechanisms of how PD-L1/PD-1 blockade synergizes with IL-2 and provides both justification and potential new targets to exploit this sensitization (Fig. 1).To explore whether PD-1 signaling regulates γ c level, Liu et al. used immunochemistry, showing an inverse correlation between PD-L1 and γ c protein level in vivo in human non-small cell lung cancer tissues.In vitro, ex vivo, and in vivo studies demonstrated that PD-L1 and PD-1 engagement resulted in decreased γ c protein levels with no effect on γ c mRNA levels in T cells, suggesting posttranscriptional regulation of γ c .