Dataset Information

Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer.

ABSTRACT: The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer (GC) associated with low HER2 positivity rate and insensitivity to chemotherapy and immune checkpoint inhibitors. Here, we identify urokinase-type plasminogen activator receptor (uPAR) as a potential therapeutic target for DGC. We have developed a novel anti-uPAR monoclonal antibody, which targets the domains II and III of uPAR and blocks the binding of urokinase-type plasminogen activator to uPAR. We show that the combination of anti-uPAR and anti-Programmed cell death protein 1 (PD-1) remarkably inhibits tumor growth and prolongs survival via multiple mechanisms, using cell line-derived xenograft and patient-derived xenograft mouse models. Furthermore, uPAR chimeric antigen receptor-expressing T cells based on the novel anti-uPAR effectively kill DGC patient-derived organoids and exhibit impressive survival benefit in the established mouse models, especially when combined with PD-1 blockade therapy. Our study provides a new possibility of DGC treatment by targeting uPAR in a unique manner.

SUBMITTER: Qin L

PROVIDER: S-EPMC9132454 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer.

Qin Long L Wang Long L Zhang Junchang J Zhou Huinian H Yang Zhiliang Z Wang Yan Y Cai Weiwen W Wen Fei F Jiang Xiangyan X Zhang Tiansheng T Ye Huili H Long Bo B Qin Junjie J Shi Wengui W Guan Xiaoying X Yu Zeyuan Z Yang Jing J Wang Qi Q Jiao Zuoyi Z

Science advances 20220525 21

The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer (GC) associated with low HER2 positivity rate and insensitivity to chemotherapy and immune checkpoint inhibitors. Here, we identify urokinase-type plasminogen activator receptor (uPAR) as a potential therapeutic target for DGC. We have developed a novel anti-uPAR monoclonal antibody, which targets the domains II and III of uPAR and blocks the binding of urokinase-type plasminogen activator to uPAR. We show that the combination ...[more]

PMID: 35613265

Similar Datasets

Project description:BackgroundThe efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma (HCC) remains poor. Although serine- and arginine-rich splicing factor (SRSF) family members play crucial roles in tumors, their impact on tumor immunology remains unclear. This study aimed to elucidate the role of SRSF10 in HCC immunotherapy.MethodsTo identify the key genes associated with immunotherapy resistance, we conducted single-nuclear RNA sequencing, multiplex immunofluorescence, and The Cancer Genome Atlas and Gene Expression Omnibus database analyses. We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems, flow cytometry, various tumor-bearing mouse models, and patient-derived organotypic tumor spheroids.ResultsSRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8+ T cell activity. Mechanistically, SRSF10 interacted with the 3'-untranslated region of MYB, enhancing MYB RNA stability, and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1 (GLUT1), hexokinase 1 (HK1), lactate dehydrogenase A (LDHA), resulting in elevated intracellular and extracellular lactate levels. Lactate accumulation induced histone lactylation, which further upregulated SRSF10 expression. Additionally, lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages, thereby activating transcription and enhancing pro-tumor macrophage activity. M2 macrophages, in turn, inhibited the enrichment of CD8+ T cells and the proportion of interferon-γ+CD8+ T cells in the tumor microenvironment (TME), thus creating an immunosuppressive TME. Clinically, SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) in both murine and human preclinical models.ConclusionsThe SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance. Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.

Project description:Cancer-associated fibroblasts (CAFs) are one of the components in tumor microenvironment (TME) that can facilitate tumor progression, invasion, and metastasis directly through tumor-CAF interactions, or indirectly by crosstalking with tumor infiltrating immune cells and inducing immunosuppressive TME. Indeed, high stromal signature has been associated with reduced therapeutic efficacy and resistance to Immune Checkpoint Blockade. AEBP1 is highly expressed in myofibroblast cells whose expression is further upregulated in activated fibroblasts and the extracellular matrix (ECM)-producing CAFs. AEBP1 has two alternatively spliced isoforms that the extracellular isoform binds to collagen and promotes collagen remodeling, and the intracellular isoform modulates transcription and signaling. We observed expression of both isoforms of AEBP1 in primary human CAFs. Our data showed that combined knock out (KO) of both isoforms of AEBP1 by gene editing technology decreased CAF proliferation, collagen gel contractility and CAF-mediated tumor cell proliferation in vitro. Pan AEBP1 KO mouse fibroblasts also showed reduced activity in vitro and in vivo in the co-implantation mouse model. We found that knocking out both isoforms of AEBP1 downregulated the collagen biosynthesis and ECM organization related pathways in both mouse fibroblasts and primary human CAFs through RNA sequencing studies. In addition, loss of AEBP1 in fibroblasts impacted tumor cell phenotypes resulting in significant decrease of tumor cells with,with epithelial-mesenchymal transition signature in the co-implantation mouse model. Furthermore, AEBP1 KO in CAFs enhanced the anti-PD-1 induced effector T cell activity and the anti-PD-1 efficacy in this co-implantation model. Altogether, our results demonstrate that AEBP1 is important in regulating CAF function in the TME. Inhibiting AEBP1, therefore, may be a novel strategy in targeting CAF tumor-supporting activity and overcoming cancer resistance to anti-PD-1 immunotherapy.

Dataset Information

Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer.

Publications

Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets