Related Experiment Video
Updated: Aug 16, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Identification of DDX60 as a Regulator of MHC-I Class Molecules in Colorectal Cancer
Nina Geng1,2, Tuo Hu1,3, Chunbo He1
1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Abstract:
Immune checkpoint blockade (ICB) therapies induce durable responses in approximately 15% of colorectal cancer (CRC) patients who exhibit microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR). However, more than 80% of CRC patients do not respond to current immunotherapy. The main challenge with these patients is lack of MHC-I signaling to unmask their cancer cells so the immune cells can detect them. Here, we started by comparing IFNγ signature genes and MHC-I correlated gene lists to determine the potential candidates for MHC-I regulators. Then, the protein expression level of listed potential candidates in normal and cancer tissue was compared to select final candidates with enough disparity between the two types of tissues. ISG15 and DDX60 were further tested by wet-lab experiments. Overexpression of DDX60 upregulated the expression of MHC-I, while knockdown of DDX60 reduced the MHC-I expression in CRC cells. Moreover, DDX60 was downregulated in CRC tissues, and lower levels of DDX60 were associated with a poor prognosis. Our data showed that DDX60 could regulate MHC-I expression in CRC; thus, targeting DDX60 may improve the effects of immunotherapy in some patients.
Insights
Immune checkpoint blockade therapy benefits few colorectal cancer patients. Researchers identified DDX60 as a regulator of MHC-I signaling, suggesting it could enhance immunotherapy effectiveness in non-responders.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint blockade (ICB) therapy benefits only 15% of colorectal cancer (CRC) patients with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR).
- Over 80% of CRC patients do not respond to immunotherapy due to insufficient MHC-I signaling, hindering immune cell detection of cancer cells.
Purpose of the Study:
- To identify novel regulators of MHC-I expression in colorectal cancer.
- To investigate the potential of targeting these regulators to improve immunotherapy response rates in CRC patients.
Main Methods:
- Comparative analysis of IFNγ signature genes and MHC-I correlated gene lists.
- Protein expression analysis of candidate regulators in normal and tumor tissues.
- Wet-lab experiments involving overexpression and knockdown of DDX60 in CRC cells.
Main Results:
- DDX60 was identified as a key regulator of MHC-I expression.
- Overexpression of DDX60 increased MHC-I expression, while its knockdown decreased it in CRC cells.
- DDX60 was found to be downregulated in CRC tissues, with lower levels correlating with poor prognosis.
Conclusions:
- DDX60 plays a crucial role in regulating MHC-I expression in colorectal cancer.
- Targeting DDX60 presents a potential strategy to enhance the efficacy of immunotherapy in a subset of CRC patients.
