Waking Immune-Resistant Tumors With Neddylation

Authors

Kristin Huntoon
Wen Jiang
Betty Ys Kim

Publication Date

2-15-2023

Journal

The Journal of Clinical Investigation

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.

Keywords

Humans, CD47 Antigen, Receptors, Immunologic, Phagocytosis, Neoplasms, Protein Tyrosine Phosphatases, Immunotherapy, Antigens, Differentiation

Comments

PMID: 36787255

DOI

10.1172/JCI167894

PMID

36787255

PMCID

PMC9927922

PubMedCentral® Posted Date

February 2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes