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

基本信息

批准号：
10224146
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
项目类别：
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/10224146
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 Exposure to Fibrosis Future Gene Expression Genetic Transcription Goals Human Immune Immune Evasion Immunofluorescence Immunologic Immunotherapy Integrin Inhibition Integrin alphaV 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 beta 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 integrin beta6 lymph nodes mouse model neoplastic cell patient subsets programs refractory cancer resistance mechanism response small molecule inhibitor spatial relationship therapeutic target transcription factor triple-negative invasive breast carcinoma tumor tumor-immune system interactions

项目摘要

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 αV and SOX4 proteins (ITGAV and SOX4 genes) render tumor cells resistant to killing by cytotoxic T cells. Integrin αVβ6 and SOX4 form a resistance pathway that is particularly relevant to TNBC: Integrin αVβ6 releases TGFβ from an inactive latent complex by a force-dependent mechanism, and active TGFβ induces expression of the SOX4 transcription factor that inhibits T cell-mediated tumor immunity. The integrin αVβ6 heterodimer is expressed at a low level by healthy epithelial cells, but its expression is highly upregulated in many epithelial cancers, including TNBC. TGFβ 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 TGFβ for cancer immunotherapy. Our preliminary data demonstrate that an integrin αVβ6 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 αVβ6 – 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 αVβ6 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 αVβ6 – 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 αVβ6 – 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 αVβ6/SOX4 expression and T cell infiltration in human TNBC specimens. High-affinity integrin αVβ6 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.

三阴性乳腺癌主要免疫抵抗途径的治疗靶向抽象的检查点封锁可为部分三阴性乳腺癌患者带来适度的生存获益癌症（TNBC），但目前大多数患者未能从免疫疗法中受益。编码整合素 αV 和 SOX4 蛋白的基因（ITGAV 和 SOX4 基因）使肿瘤细胞对细胞毒性 T 细胞的杀伤作用与整合素 αVβ6 和 SOX4 形成的耐药途径特别相关。 TNBC：整合素αVβ6通过力依赖性机制从失活的潜在复合物中释放TGFβ，并且活性 TGFβ 诱导 SOX4 转录因子的表达，抑制 T 细胞介导的肿瘤免疫。整合素αVβ6异二聚体在健康上皮细胞中表达水平较低，但其表达量在许多上皮癌中高度上调，包括 TNBC，它是一种重要的免疫抑制因子。人类肿瘤中的细胞因子，但由于其在不同细胞类型和细胞中的多效性生物学而难以靶向这种方法为更有选择性地靶向癌症的 TGFβ 提供了机会。我们的初步数据表明，整合素 αVβ6 阻断单克隆抗体可抑制 SOX4。该抗体能够使 TNBC 细胞对细胞毒性 T 细胞敏感，从而带来显着的生存益处。在目标 1 中，我们将研究两种对检查点封锁具有抵抗力的侵袭性 TNBC 小鼠模型。整合素 αVβ6 – SOX4 耐药途径作为侵袭性和高度转移性免疫治疗靶点特别是，我们将研究整合素 αVβ6 的抑制如何诱导大量的 TNBC 小鼠模型。 CD8 T 细胞涌入 T 细胞浸润不良的 TNBC 中。在目标 2 中，我们将研究 TNBC。整合素αVβ6-SOX4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 SOX4 转录因子抑制多种基因的表达肿瘤细胞中的先天免疫途径，包括胞质 dsRNA 和 dsDNA 传感途径作为1型干扰素反应途径，我们将定义SOX4的直接转录靶点并进行研究。 SOX4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抵抗在目标 3 中，我们将研究整合素 αVβ6 – SOX4 通路在人类 TNBC 中的重要性。假设这种耐药途径抑制了人类 TNBC 中的 T 细胞浸润，因此我们将检查人 TNBC 中整合素 αVβ6/SOX4 表达与 T 细胞浸润之间的空间关系高亲和力整合素 αVβ6 抗体和小分子抑制剂已在体内进行测试。因此，此处描述的研究可以为纤维化适应症提供科学依据。在 TNBC 和其他上皮来源的人类癌症中测试此类抑制剂。