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

三阴性乳腺癌主要免疫耐药通路的靶向治疗 摘要 检查点封锁导致三阴性乳房患者亚组患者的适度生存受益 癌症(TNBC)，但目前大多数患者未能从免疫疗法中受益。我们最近发现， 编码整合素ITGAV和SOX4蛋白的基因(α和SOX4基因)使肿瘤细胞对 细胞毒性T细胞的杀伤作用。整合素αVβ6和SOX4形成一条抗性途径，该途径与 TnBC：整合素αVβ6以力依赖机制从失活的潜伏复合体中释放转化生长因子β 活化的转化生长因子β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异源二聚体在健康的上皮细胞中低水平表达，但其表达 在包括TNBC在内的许多上皮性癌中高度上调。转化生长因子β是一种重要的免疫抑制剂。 细胞因子在人类肿瘤中的作用，但由于其在不同细胞类型和不同细胞类型中的多效性生物学作用而难以靶向 纸巾。这种方法为更有选择性地靶向转化生长因子β治疗癌症提供了机会。 免疫疗法。我们的初步数据表明，整合素αVβ6封闭单抗抑制SOX4 表达并增强TNBC细胞对细胞毒T细胞的敏感性。这种抗体对生存有很大的好处。 在两种对检查点封锁具有抵抗力的侵袭性TNBC小鼠模型中。在目标1中，我们将研究 整合素αVβ6-SOX4耐药通路作为侵袭性和高转移肿瘤免疫治疗靶点的研究 TNBC小鼠模型的建立。特别是，我们将研究抑制整合素αVβ6是如何诱导大量 CD8 T细胞进入T细胞渗透较差的TNBCs。在目标2中，我们将调查 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转录因子抑制了来自多个 肿瘤细胞中的先天免疫通路，包括胞浆dsRNA和dsDNA传感通路 作为1型干扰素反应途径。我们将定义Sox4的直接转录靶点并研究 Sox4如何与其他转录因子协同作用使肿瘤细胞对T细胞介导的肿瘤产生抵抗 豁免权。在目的3中，我们将研究整合素αVβ6-Sox4通路在人肿瘤细胞中的意义。我们的 假设这种耐药途径抑制了T细胞在人TNBC中的渗透，因此我们将 人肿瘤细胞中整合素αVβ6/SOX4的表达与T细胞浸润的空间关系 标本。高亲和力整合素αVβ6抗体和一种小分子抑制剂已经在 纤维化适应症的临床试验。因此，这里描述的研究可以提供科学的理由 在TNBC和其他起源于上皮的人类癌症中测试这种抑制物。

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.