Waking immune-resistant tumors with neddylation
Kristin Huntoon, … , Wen Jiang, Betty Y.S. Kim
Kristin Huntoon, … , Wen Jiang, Betty Y.S. Kim
Published February 15, 2023
Citation Information: J Clin Invest. 2023;133(4):e167894. https://doi.org/10.1172/JCI167894.
View: Text | PDF
Commentary

Waking immune-resistant tumors with neddylation

Abstract

The CD47/signal regulatory protein α (SIRPα) axis, which functions as an inhibitory phagocytosis checkpoint, also serves as a key mediator in cancer immune evasion. Many cancers, including colorectal cancer (CRC), exploit the expression of CD47 to escape phagocytic clearance and activate the innate immune system. Previous work has indicated that distinct paradigms of posttranslational modifications mediate the regulatory mechanisms of the CD47/SIRPα axis. In this issue of the JCI, Li et al. show that neddylation, a ubiquitin-like modification, inactivates Src homology region 2–containing protein tyrosine phosphatase 2 (SHP2), a downstream target of this pathway. They further show that inhibition of SHP2 sensitizes CRC cells to immunotherapies to which they were previously resistant. Collectively, the results underscore the need for cotargeting SHP2 and immune checkpoints (e.g., programmed death 1 [PD1]) in CRC and possibly other immunotherapy-resistant tumors.

Authors

Kristin Huntoon, Wen Jiang, Betty Y.S. Kim

×

Figure 1

A proposed mechanism of action of the CD47/SIRPα/SHP2 signaling complex involves neddylation.

Options: View larger image (or click on image) Download as PowerPoint
A proposed mechanism of action of the CD47/SIRPα/SHP2 signaling complex ...
(A) SIRPα is a transmembrane protein that contains three Ig-like domains in its extracellular region and two tyrosine phosphorylation sites within its cytoplasmic region. CD47 on tumor cells binds SIRPα on macrophages, promoting tyrosine phosphorylation of SIRPα and its subsequent binding to protein tyrosine phosphatases. This pathway is mediated by the deneddylation of SHP2 via SENP8, which activates the SIRPα-associated phosphatases. Specifically, SIRPα’s cytoplasmic ITIM facilitates this signaling sequence,resulting in the inhibition of phagocytosis (operating as a “do-not-eat-me” signal). (B) When SHP2 is neddylated, it cannot bind to the ITIM of SIRPα and thus promotes phagocytosis of the tumor cell.