Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma

Abstract

Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting.

Wnt Signaling Cascade in Dendritic Cells and Regulation of Anti-tumor Immunity

“…Emerging studies have shown an important role for Wnts in regulating maturation and activation of tumor-associated DCs. Earlier ex vivo studies on human and murine DCs have shown that exposure to Wnt1, Wnt3a, and Wnt5a that activates β-catenin can program DCs to a regulatory state with decreased expression of co-stimulatory molecules (17,20,21). Similar observations were made with murine and human DCs upon blocking GSK3β activation (a negative regulator of β-catenin) or activating β-catenin in DCs (55,56).…”

“…Tumor growth, migration, and metastasis (43)(44)(45) Immune cell exclusion (17,27,28,(46)(47)(48) augmented DCs activation with an increased expression of costimulatory molecules and decreased expression of co-inhibitory molecules (21,22,56). Collectively, these studies show that Wnt/β-catenin signaling interferes with DC maturation and activation in the TME.…”

“…Tumor DCs-deficient in LRP5/6 or β-catenin is more potent in capturing and cross-presenting TAAs to CD8 + T cells (21)(22)(23)(24) Tumor DCs lacking LRP5/6 or β-catenin are programmed to induce Th1/Th17 cells (21,22) Active Wnt/β-catenin signaling affects trafficking of DCs to tumors and TDLNs (17) Active Wnt/β-catenin signaling in tumor DCs regulates metabolic pathways involving FAO, vitamin A, and tryptophan to induce regulatory T cell (Treg) response (21)(22)(23)(24)(25)(26) Wnt-signaling in tumor DCs suppresses chemokines that are critical of recruitment and accumulation of CTL in the TME (17,27,28)…”

“…Tumor DCs also produce chemokines that are critical for accumulation of T cells within the TME (5). A recent study on lung adenocarcinoma (LUND) has shown that tumor DC-intrinsic Wnt signaling plays a key role in blocking T cell infiltration into the tumors and driving cross-tolerance to tumor antigens (17). Mechanistically, Wnt1-mediated β-catenin signaling in tumor DCs resulted in transcriptional silencing of CC/CXC chemokines that are critical for recruiting effector T cells to the TME (17).…”

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+T cells

“…Chemokines through their G proteincoupled receptors (GPCRs) are major drivers of T-cell chemotaxis and trafficking and keep attracting interest as potential therapeutic targets in immuno-oncology (Chow and Luster, 2014;Do et al, 2020;Vilgelm and Richmond, 2019). Tumors evolve various strategies to evade T-cell infiltration via activation of oncogenic signaling pathways, for instance by suppressing chemokine production and signaling and/or by secreting antimigratory molecules such as Wnt ligands and TGF (Batlle and Massague, 2019;Hinshaw and Shevde, 2019;Kerdidani et al, 2019;Spranger et al, 2015). Yet, much remains to be learned about soluble factors and GPCR ligands that counteract T-cell chemotaxis and tumor infiltration.…”