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.

靶向治疗三阴性乳腺癌的主要免疫耐药途径 摘要 检查点阻断可使一部分三阴性乳腺癌患者获得中度生存获益 癌症（TNBC），但大多数患者目前未能受益于免疫疗法。我们最近发现， 编码整联蛋白ITGAV和SOX 4蛋白的基因（ITGAV和SOX 4基因）使肿瘤细胞对抗肿瘤药物具有抗性。 细胞毒性T细胞的杀伤。整合素BV 6和S 0X 4形成抗性途径，其特别相关于 TNBC：整联蛋白TGF β 6通过力依赖性机制从无活性的潜伏复合物中释放TGF β， 活性TGF β诱导抑制T细胞介导的肿瘤免疫的SOX 4转录因子的表达。 健康上皮细胞表达低水平的整合素α V β 6异二聚体，但其表达水平与正常上皮细胞的表达水平一致。 在许多上皮癌中高度上调，包括TNBC。TGF β是一种重要的免疫抑制剂， 细胞因子，但由于其在不同细胞类型中的多效性生物学， 组织中这种方法为更有选择性地靶向TGF β 1治疗癌症提供了机会 免疫疗法我们的初步数据表明，一种整合素β V6阻断单克隆抗体抑制SOX 4， 表达并使TNBC细胞对细胞毒性T细胞敏感。这种抗体赋予一个实质性的生存效益 在对检查点阻断具有抗性的两种侵袭性TNBC小鼠模型中。在目标1中，我们将研究 作为侵袭性和高转移性肿瘤免疫治疗靶点的整合素VEGF 6 -SOX 4抗性途径 TNBC小鼠模型。特别是，我们将研究如何抑制整联蛋白p53 V β 6诱导实质性的 CD 8 T细胞流入T细胞浸润不良的TNBC。在目标2中，我们将研究 整联蛋白VEGF 6 -SOX 4途径抑制T细胞介导的肿瘤免疫的分子机制。 初步数据表明，SOX 4转录因子抑制来自多种细胞的基因表达， 肿瘤细胞中的先天免疫途径，包括胞质dsRNA和dsDNA传感途径以及 作为1型干扰素反应途径。我们将定义SOX 4的直接转录靶点，并研究 SOX 4如何与其他转录因子合作使肿瘤细胞对T细胞介导的肿瘤产生抗性 免疫力在目的3中，我们将研究人TNBC中整联蛋白p53 Vp 66-S 0X 4途径的意义。我们 假设是这种抗性途径抑制人TNBC中的T细胞浸润，因此我们将 检查人TNBC中整联蛋白G4 V6/SOX 4表达和T细胞浸润之间的空间关系 标本高亲和力整联蛋白HIV-H6抗体和一种小分子抑制剂已经在美国进行了测试。 纤维化适应症的临床试验。因此，这里描述的研究可以为以下方面提供科学依据： 在TNBC和其他上皮来源的人类癌症中测试这种抑制剂。