DDX54 downregulation enhances anti-PD1 therapy in immune-desert lung tumors with high tumor mutational burden
Menée à l'aide notamment de données du projet "The Cancer Genome Atlas", cette étude met en évidence le rôle des hélicases DDX54 dans la régulation de l'échappement immunitaire des cancers du poumon présentant une charge mutationnelle élevée mais pas d'infiltration lymphocytaire et démontre que l'inhibition de ces hélicases améliore la sensibilité des cellules cancéreuses aux anti-PD1
Although a high mutational burden is an FDA-approved biomarker for immune checkpoint inhibitors (ICIs), some immune-desert lung cancers remain resistant despite a high tumor mutational burden (TMB-H). We identified DDX54 as a master regulator in immune-desert lung cancer with a high mutational burden, whose knockdown reduces resistance to ICIs. DDX54 promotes an immune-evasive tumor microenvironment (TME) in lung cancer by inducing CD38 and CD47 expression and inhibiting immune cell infiltration, thereby reducing the efficacy of ICIs. DDX54 knockdown combined with anti-PD-1 treatment increases T cell, NK cell, and antitumor monocyte infiltration, sensitizing tumors to anti-PD-1 therapy. These findings suggest that targeting DDX54 can reprogram immune-desert tumors into immune-inflamed tumors, potentially enhancing immunotherapy efficacy in cancer patients. 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.