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DDX54 downregulation enhances anti-PD1 therapy in immune-desert lung tumors with high tumor mutational burden
Jeong-Ryeol Gong1, Jungeun Lee1, Younghyun Han1
1Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
Abstract:
High tumor mutational burden (TMB-H) is a predictive biomarker for the responsiveness of cancer to immune checkpoint inhibitor (ICI) therapy that indicates whether immune cells can sufficiently recognize cancer cells as nonself. However, about 30% of all cancers from The Cancer Genome Atlas (TCGA) are classified as immune-desert tumors lacking T cell infiltration despite TMB-H. Since the underlying mechanism of these immune-desert tumors has yet to be unraveled, there is a pressing need to transform such immune-desert tumors into immune-inflamed tumors and thereby enhance their responsiveness to anti-PD1 therapy. Here, we present a systems framework for identifying immuno-oncotargets, based on analysis of gene regulatory networks, and validating the effect of these targets in transforming immune-desert into immune-inflamed tumors. In particular, we identify DEAD-box helicases 54 (DDX54) as a master regulator of immune escape in immune-desert lung cancer with TMB-H and show that knockdown of DDX54 can increase immune cell infiltration and lead to improved sensitivity to anti-PD1 therapy.
Insights
High tumor mutational burden (TMB-H) predicts immune checkpoint inhibitor (ICI) therapy response. Researchers identified DDX54 as a target to convert immune-desert tumors into inflamed tumors, improving anti-PD1 therapy sensitivity.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- High tumor mutational burden (TMB-H) predicts response to immune checkpoint inhibitors (ICIs).
- However, some TMB-H cancers are immune-desert, lacking T-cell infiltration, limiting ICI efficacy.
- Understanding and overcoming immune desert phenotypes is crucial for enhancing cancer immunotherapy.
Purpose of the Study:
- To develop a systems framework for identifying immuno-oncotargets.
- To validate targets that can transform immune-desert tumors into immune-inflamed tumors.
- To investigate DDX54 as a potential therapeutic target in TMB-H immune-desert lung cancer.
Main Methods:
- Analysis of gene regulatory networks to identify master regulators of immune escape.
- In silico and experimental validation of identified targets.
- Assessment of immune cell infiltration and anti-PD1 therapy sensitivity following target modulation.
Main Results:
- A systems framework successfully identified key immuno-oncotargets.
- DDX54 was identified as a master regulator of immune escape in TMB-H immune-desert lung cancer.
- Knockdown of DDX54 increased immune cell infiltration and enhanced sensitivity to anti-PD1 therapy.
Conclusions:
- DDX54 is a promising target for converting immune-desert tumors into immune-inflamed phenotypes.
- Targeting DDX54 could improve the efficacy of anti-PD1 therapy in specific cancer types.
- The developed framework offers a novel approach for discovering new cancer immunotherapy targets.
