Gonga and Lee et al. focused on mechanisms of ICI resistance in immune-desert lung tumors that lack T cell infiltration, despite having a high mutational burden (TMB-H), by analyzing gene regulatory networks in TMB-H lung tumors from TCGA. DDX54 was identified as a master regulator of immune-desert phenotypes via induction of immunosuppressive oncogenic Myc and Wnt pathways, EMT, cancer stemness, and CD38 and CD47 expression. In TMB-H syngeneic mouse lung models, DDX54 knockdown combined with anti-PD-1 increased immune cell infiltration (T cells, NK cells, M1 monocytes, and dendritic cells) and improved sensitivity to anti-PD-1.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (2) Department of Bio and Brain Engineering, Kore
Author Info: (1) Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (2) Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (3) Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (4) Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
