概要: Lung adenocarcinoma (LUAD)-derived oncogenic Wnts increase cancer cell proliferative/stemness potential, but whether they also impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. Wnt1 correlated strongly with tolerogenic genes on the TCGA expression data. In another cohort, Wnt1 was inversely associated with T cell abundance. Altering Wnt1 expression profoundly affected growth of murine lung adenocarcinomas and this was strongly dependent on conventional dendritic cells and T cells. Mechanistically, Wnt1 lead to transcriptional silencing of CC/CXC chemokines in dendritic cells and T cell cross-tolerance. Wnt-target genes were up-regulated in human intratumoral dendritic cells and decreased upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-loaded nanoparticles as single therapy or part of combinatorial immunotherapies acted at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 enhances adaptive immune rejection of lung adenocarcinomas and highlight its potential targeting as a novel therapeutic strategy
项目整体设计: RNAseq data of two DC subsets of 4 patients with lung adenocarcinomas (LUADs).
Primary LUADs and juxtatumor lung tissues were pushed through 40m strainers (Corning). CD45+ cells were magnetically enriched using CD45 Microbeads (Miltenyi Biotech), stained as described in Figure S16 and sorted in RL buffer (NorgenBioteck).
提取方案:
RNA purification was performed with Norgen kit (NorgenBioteck) and cDNA synthesis with SMARter kit for Illumina Sequencing-HV(Clontech).
建库方案:
Sequencing was performed in Illumina HiSeq 2500, the average depth is 15 million reads of 50-nt-length reads per sample. Library (paiRNAends fragments), sequencing and sequencing quality control were performed by the Institut Curie NGS plateform.
测序信息
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poly(A)+ RNA
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PAIRED
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-
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ILLUMINA
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Illumina HiSeq 2500
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Unspecific
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文章
Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma.
