Project description:Comparing two agonists of interleukin-2 (IL-2), IL-2wt and IL-2nα, differentially reshape the tumor microenvironment (TME). To more comprehensively explore the mechanisms by which the two different IL-2R agonists regulate the TME, we performed single-cell RNA sequencing (scRNA-seq) on immune cells isolated from tumors. We clustered the 18,455 tumor-infiltrating immune cells into 5 populations, and found marked expansion of T cell populations as well as contraction of mononuclear phagocyte populations in both IL-2wt and IL-2nα treated tumors compared with immunoglobulin G (IgG) controls.
Project description:Tumor endothelial cells (TECs) and corresponding normal endothelial cells (NECs) were isolated from 12 different human colocrectal carcinoma (CRC) patients with different prognostic tumor microenvironments (TME: Th1-TME vs Control-TME).
Project description:Recombinant cytokines have limited anti-cancer efficacy mostly due to narrow therapeutic window and systemic adverse effects. IL-18 is an inflammasome induced proinflammatory cytokine that enhances T and NK cell activity and stimulates IFNg production. The activity of IL-18 is naturally blocked by a high affinity endogenous binding protein (IL-18BP). IL-18BP is induced in the tumor microenvironment (TME) in response to IFNg upregulation in a negative feedback mechanism. In this study we found that IL-18 is upregulated in the TME compared to the periphery across multiple human tumors and most of it is bound to IL-18BP. Bound IL-18 levels were largely above the amount required for T cell activation in vitro, implying that releasing IL-18 in the TME could lead to potent T cell immune activation. To restore the activity of endogenous IL-18 we generated COM503, a high affinity anti-IL-18BP antibody (Ab), that blocks the IL-18BP:IL-18 interaction and displaces pre-complexed IL-18 to enhance T cell and NK cell activation. In vivo, administration of a surrogate anti-IL-18BP Ab, either alone or in combination with anti-PD-L1 Ab, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, anti-IL-18BP Ab induced pronounced TME-localized immune modulation including an increase in polyfunctional non-exhausted T and NK cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL-18BP using an Ab is a promising novel approach to harness cytokine biology for the treatment of cancer.
Project description:To find potential lncRNAs participating in the regulation of microglial polarization, we employed microarray screening to find differentially expressed lncRNAs between resting and IL-4 stimulated primary cultured microglia
Project description:The tumor microenvironment (TME) is a complex mixture of tumor cells, immune cells, endothelial cells and fibroblastic stroma cells (FSC). While cancer-associated fibroblasts are generally seen as a tumor-promoting entity, it is conceivable that distinct FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intra-tumoral injection of a recombinant LCMV-based vaccine vector (r3LCMV) expressing the melanocyte differentiation antigen TRP2 results in T cell-dependent eradication of melanomas. Analysis of the TME revealed that viral vector transduction precipitates activation of particular FSC subsets. Using single-cell RNA-seq analysis, we identified a Cxcl13-expressing FSC population with a pronounced immune-stimulatory signature and increased expression of the inflammatory cytokine IL-33. Genetic ablation of Il33 in Cxcl13-Cre+ FSC impeded functionality of intratumoral T cells and consequently tumor control. Thus, reprogramming of distinct FSC subsets in the TME through LCMV-based vectors efficiently promotes tumor eradication by locally sustaining the activity of tumor-specific T cells.
Project description:We hypothesized that IL-33 created Tc1-like condition in the modifying tumor microenvironment (TME). RNA-seq analysis of dendritic cells (DCs) showed the elevation of Il1rl1 and SEMA4A by IL-33, the latter of which was confirmed by qPCR, without significant upregulation of IL-12.
Project description:Resistance to DNA damage is one of the primary mechanisms by which tumor cells evade the effects of standard chemotherapeutic agents and radiotherapy. Dynamic and complex interactions between the tumor microenvironment (TME) and tumor cells critically influence the DNA damage response. Interleukin-33 (IL-33) is a multifunctional cytokine secreted at high levels in response to cellular damage and stress. Recently, increasing evidence has suggested that IL-33 plays a key role in promoting the therapeutic resistance of tumors. However, the actual source of IL-33 during cancer therapy and how IL-33 contributes to a resistant TME remain incompletely understood. In this study, we found that both cancer-associated fibroblasts (CAFs) and tumor cells treated with DNA damage-inducing agents expressed and secreted high levels of IL-33, subsequently leading to enhanced DNA damage repair efficacy. Mechanistically, nuclear IL-33 primarily functions as a transcriptional co-activator of homologous recombination repair (HRR) genes, whereas the active form of IL-33 can drive the non-homologous end joining (NHEJ) pathway via the canonical IL-33/ST2 axis. Overall, we demonstrated that IL-33 plays a key role in mediating a DNA damage-resistant TME, which could represent a potential therapeutic vulnerability in chemoresistant cancer cells
Project description:To goal of the experiment is to assess whether we can profile enough cells corresponding to the host TME. In this PDX model, most of the cells correspond to the xenograft material, with limited amounts of host TME cells. To this aim we loaded 16 times more cells hybridized with the mouse probe set compared to the human hybridization.