Targeting of a Major Immune Evasion Pathway in Triple-negative Breast Cancer

靶向三阴性乳腺癌的主要免疫逃避途径

• 批准号: 10029035
• 负责人: Kai W Wucherpfennig
• 金额: $ 48.54万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10029035
• 关键词: Affinity; Antibodies; Biological Markers; Biology; Blood Circulation; Breast Cancer Cell; Breast Cancer Model; CD8-Positive T-Lymphocytes; CRISPR screen; Carcinoma; Cell Density; Cells; Cellular Immunity; Clinical Trials; Clinical Trials Design; Color; Complex; Cytotoxic T-Lymphocytes; Data; Disease; Double-Stranded RNA; Epithelial; Epithelial Cells; Epithelium; Exposure to; Fibrosis; Future; Gene Expression; Genetic Transcription; Goals; Human; Immune; Immune Evasion; Immunofluorescence Immunologic; Immunotherapy; Integrin Inhibition; Integrins; Interferons; Malignant Neoplasms; Mediating; Modeling; Molecular; Monoclonal Antibodies; Mus; Mutation; Neoplasm Metastasis; Pathway interactions; Patient Selection; Patients; Population; Primary Neoplasm; Proteins; Resistance; Role; SOX4 gene; Specimen; Stimulator of Interferon Genes; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Tissues; Transforming Growth Factor alpha; Tumor Immunity; Tumor-infiltrating immune cells; base; cancer immunotherapy; cell type; clinically relevant; cytokine; ds-DNA; epithelial to mesenchymal transition; gene discovery; genome-wide; immune checkpoint blockade; immune resistance; inhibitor/antagonist; innate immune pathways; lymph nodes; mouse model; neoplastic cell; patient subsets; programs; resistance mechanism; response; small molecule inhibitor; spatial relationship; therapeutic target; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor-immune system interactions

Therapeutic Targeting of a Major Immune Resistance Pathway in Triple-negative Breast Cancer Abstract Checkpoint blockade results in moderate survival benefit in a subset of patients with triple-negative breast cancer (TNBC) but most patients currently fail to benefit from immunotherapy. We recently discovered that the genes encoding the integrin V and SOX4 proteins (ITGAV and SOX4 genes) render tumor cells resistant to killing by cytotoxic T cells. Integrin V6 and SOX4 form a resistance pathway that is particularly relevant to TNBC: Integrin V6 releases TGF from an inactive latent complex by a force-dependent mechanism, and active TGF induces expression of the SOX4 transcription factor that inhibits T cell-mediated tumor immunity. The integrin V6 heterodimer is expressed at a low level by healthy epithelial cells, but its expression is highly upregulated in many epithelial cancers, including TNBC. TGF is an important immunosuppressive cytokine in human tumors, but has been difficult to target due to its pleiotropic biology in different cell types and tissues. This approach provides an opportunity for more selective targeting of TGF for cancer immunotherapy. Our preliminary data demonstrate that an integrin V6 blocking mAb inhibits SOX4 expression and sensitizes TNBC cells to cytotoxic T cells. This antibody confers a substantial survival benefit in two aggressive mouse models of TNBC that are resistant to checkpoint blockade. In Aim 1, we will study the integrin V6 – SOX4 resistance pathway as an immunotherapy target in aggressive and highly metastatic mouse models of TNBC. In particular, we will examine how inhibition of integrin V6 induces a substantial influx of CD8 T cells into TNBCs that are poorly infiltrated by T cells. In Aim 2, we will investigate the molecular mechanisms by which the integrin V6 – SOX4 pathway inhibits T cell-mediated tumor immunity. Preliminary data demonstrate that the SOX4 transcription factor inhibits expression of genes from multiple innate immune pathways in tumor cells, including the cytosolic dsRNA and dsDNA sensing pathways as well as the type 1 interferon response pathway. We will define the direct transcriptional targets of SOX4 and study how SOX4 cooperates with other transcription factors to render tumor cells resistant to T cell-mediated tumor immunity. In Aim 3, we will study the significance of the integrin V6 – SOX4 pathway in human TNBC. Our hypothesis is that this resistance pathway inhibits T cell infiltration in human TNBC, and we will therefore examine the spatial relationship between integrin V6/SOX4 expression and T cell infiltration in human TNBC specimens. High-affinity integrin V6 antibodies and a small molecule inhibitor are already being tested in clinical trials for fibrosis indications. The studies described here could thus provide the scientific rationale for testing of such inhibitors in TNBC and other human cancers of epithelial origin.

三阴性乳腺癌中主要免疫抗性途径的治疗靶向 抽象的 检查点封锁导致三阴性乳房患者的一部分中等生存益处 癌症（TNBC），但大多数患者目前无法从免疫疗法中受益。我们最近发现 编码整联蛋白V和SOX4蛋白（ITGAV和SOX4基因）的基因使肿瘤细胞具有抗性 通过细胞毒性T细胞杀死。整联蛋白v6和sox4形成了一种抗性途径，与 TNBC：整联蛋白v6通过依赖力的机制从不活动的潜在复合物中释放出TGF，并且 活性TGF诱导SOX4转录因子的表达，从而抑制T细胞介导的肿瘤免疫抑制性。 整联蛋白v6异二聚体由健康的上皮细胞在低水平表达，但其表达是 包括TNBC在内的许多上皮癌中高度上调。 TGF是重要的免疫抑制 人肿瘤中的细胞因子，但由于其多效生物学在不同的细胞类型和 组织。这种方法为TGF进行更有选择性的靶向癌症提供了机会 免疫疗法。我们的初步数据表明，整联蛋白v6阻断mAb抑制SOX4 表达并感觉到TNBC细胞对细胞毒性T细胞。这种抗体承认了可观的生存益处 在两个具有抗检查点阻滞性的TNBC的攻击性小鼠模型中。在AIM 1中，我们将学习 整联蛋白v6 - SOX4抗性途径是一种侵略性和高度转移性的免疫疗法靶标 TNBC的鼠标模型。特别是，我们将研究整联蛋白v6的抑制如何诱导大量 CD8 T细胞对TNBC的影响，TNBC被T细胞浸润的TNBC。在AIM 2中，我们将调查 整联蛋白V6 - SOX4途径抑制T细胞介导的肿瘤免疫抑制性的分子机制。 初步数据表明，Sox4转录因子抑制了来自多个的基因的表达 肿瘤细胞中的先天免疫途径，包括胞质DSRNA和DSDNA感应途径 作为1型干扰素响应途径。我们将定义Sox4的直接转录目标并进行研究 Sox4如何使用其他转录因子教练，以使肿瘤细胞具有抗T细胞介导的肿瘤的抗性 免疫。在AIM 3中，我们将研究人类TNBC中整联蛋白V6 - SOX4途径的重要性。我们的 假设是这种抗性途径抑制了人类TNBC中的T细胞浸润，因此我们将 检查人类TNBC中整合素v6/sox4表达与T细胞浸润之间的空间关系 标本。高亲和力整联蛋白v6抗体和小分子抑制剂已经在测试中 纤维化适应症的临床试验。因此，此处描述的研究可以为科学原理提供 在TNBC和其他人类上皮来源的抑制剂测试。