DDX54 inhibition enhances anti-PD1 therapy in immune-desert lung tumors with high tumor mutational burden [Xenium]
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PROVIDER: PRJNA1203202 | ENA |
REPOSITORIES: ENA
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Project description:High tumor mutational burden (TMB) is a predictive biomarker for the responsiveness of cancer to immune checkpoint inhibitor therapy that indicates whether immune cells can sufficiently recognize cancer cells as non-self. However, about 30% of all cancers from The Cancer Genome Atlas are classified as immune-desert tumors lacking T cell infiltration despite high TMB. 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 high TMB, and show that knockdown of DDX54 can increase immune cell infiltration and lead to improved sensitivity to anti-PD1 therapy.
2025-03-19 | GSE285341 | GEO
Project description:High tumor mutational burden (TMB) is a predictive biomarker for the responsiveness of cancer to immune checkpoint inhibitor therapy that indicates whether immune cells can sufficiently recognize cancer cells as non-self. However, about 30% of all cancers from The Cancer Genome Atlas are classified as immune-desert tumors lacking T cell infiltration despite high TMB. 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 high TMB, and show that knockdown of DDX54 can increase immune cell infiltration and lead to improved sensitivity to anti-PD1 therapy.
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Project description:High tumor mutational burden (TMB) is a predictive biomarker for the responsiveness of cancer to immune checkpoint inhibitor therapy that indicates whether immune cells can sufficiently recognize cancer cells as non-self. However, about 30% of all cancers from The Cancer Genome Atlas are classified as immune-desert tumors lacking T cell infiltration despite high TMB. 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 high TMB, and show that knockdown of DDX54 can increase immune cell infiltration and lead to improved sensitivity to anti-PD1 therapy.
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Project description:High tumor mutational burden (TMB) is a predictive biomarker for the responsiveness of cancer to immune checkpoint inhibitor therapy that indicates whether immune cells can sufficiently recognize cancer cells as non-self. However, about 30% of all cancers from The Cancer Genome Atlas are classified as immune-desert tumors lacking T cell infiltration despite high TMB. 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 high TMB, and show that knockdown of DDX54 can increase immune cell infiltration and lead to improved sensitivity to anti-PD1 therapy.
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Project description:DDX54 inhibition enhances anti-PD1 therapy in immune-desert lung tumors with high tumor mutational burden
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Project description:DDX54 inhibition enhances anti-PD1 therapy in immune-desert lung tumors with high tumor mutational burden [miRNA-Seq]
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Project description:DDX54 inhibition enhances anti-PD1 therapy in immune-desert lung tumors with high tumor mutational burden [bulk RNA-seq]
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Project description:Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma; However, predicting which patients will respond to immunotherapy is still unknown. In this study we analyzed pre-immunotherapy treated tumors from 52 patients with metastatic melanoma and monitored their response based on RECIST 1.1 criteria. The responders group contained 21 patients that had a complete or partial response, while the 31 non-responders had stable or progressive disease. Whole exome sequencing (WES) was used to identify biomarkers of anti-PD1 response from somatic mutations between the two groups. Variants in codons G34 and G41 in NFKBIE, a negative regulator of NF-kB, were found exclusively in the responders. NKBIE-related genes within the responder group were also enriched compared to the non-responders. Patients that harbored NFKBIE-related gene mutations also had a higher mutational burden, decreased tumor volume with treatment, and increased progression-free survival. RNA sequencing on a subsection of tumor samples identified differential expression of the TNFA signaling via NFKB pathway, which includes CD83. By overexpressing NFKBIEG34E we were able to demonstrate this mutation is related to increased NF-kB activity, including increased CD83 protein expression when compared with the wildtype. These results suggest that increased NF-kB signaling as a consequence of an NFKBIE mutation may contribute to a favorable anti-PD1 treatment response, including a possible novel role of CD83 in solid tumors.
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