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Waking immune-resistant tumors with neddylation
Kristin Huntoon1, Wen Jiang2, Betty Ys Kim1
1Department of Neurosurgery and.
The Journal of Clinical Investigation
|February 14, 2023
Summary
Colorectal cancer (CRC) evades immune attack via the CD47/SIRPα axis. Neddylation inactivates SHP2, and inhibiting SHP2 resensitizes CRC to immunotherapy, suggesting combined targeting for better cancer treatment.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- The CD47/signal regulatory protein α (SIRPα) axis is a critical immune checkpoint that cancer cells, including colorectal cancer (CRC), exploit for immune evasion.
- Posttranslational modifications regulate the CD47/SIRPα axis, impacting cancer's interaction with the innate immune system.
Purpose of the Study:
- To investigate the role of neddylation in the CD47/SIRPα pathway in colorectal cancer.
- To determine if targeting downstream effectors of this pathway can overcome immunotherapy resistance in CRC.
Main Methods:
- Investigated the effect of neddylation on SHP2 activity within the CD47/SIRPα signaling pathway.
- Assessed the impact of SHP2 inhibition on the sensitivity of CRC cells to immunotherapy.
Main Results:
- Neddylation was shown to inactivate SHP2 (Src homology region 2-containing protein tyrosine phosphatase 2), a key downstream target of the CD47/SIRPα axis.
- Inhibition of SHP2 resensitized previously resistant colorectal cancer cells to immunotherapies.
Conclusions:
- Targeting SHP2, in combination with immune checkpoint inhibitors like programmed death 1 (PD1), is a promising strategy for treating immunotherapy-resistant colorectal cancer.
- These findings may extend to other solid tumors that exhibit resistance to current immunotherapies.
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