Cancer immunotherapy shows limited efficacy against many solid tumors that originate from epithelial tissues, including triple-negative breast cancer (TNBC). We identify the SOX4 transcription factor as an important resistance mechanism to T cell-mediated cytotoxicity for TNBC cells. Mechanistic studies demonstrate that inactivation of SOX4 in tumor cells increases the expression of genes in a number of innate and adaptive immune pathways important for protective tumor immunity. Expression of SOX4 is regulated by the integrin αvβ6 receptor on the surface of tumor cells, which activates TGFβ from a latent precursor. An integrin αvβ6/8-blocking monoclonal antibody (mAb) inhibits SOX4 expression and sensitizes TNBC cells to cytotoxic T cells. This integrin mAb induces a substantial survival benefit in highly metastatic murine TNBC models poorly responsive to PD-1 blockade. Targeting of the integrin αvβ6-TGFβ–SOX4 pathway therefore provides therapeutic opportunities for TNBC and other highly aggressive human cancers of epithelial origin.

癌症免疫疗法对许多源自上皮组织的实体瘤（包括三阴性乳腺癌 (TNBC)）的疗效有限。我们将 SOX4 转录因子确定为 T 细胞介导的 TNBC 细胞细胞毒性的重要抗性机制。机制研究表明，肿瘤细胞中 SOX4 的失活增加了许多对保护性肿瘤免疫很重要的先天性和适应性免疫途径中基因的表达。SOX4 的表达由肿瘤细胞表面的整合素 αvβ6 受体调节，该受体从潜在的前体激活 TGFβ。一种整合素 αvβ6/8 阻断单克隆抗体 (mAb) 可抑制 SOX4 表达并使 TNBC 细胞对细胞毒性 T 细胞敏感。这种整合素 mAb 在对 PD-1 阻断反应不佳的高转移性鼠 TNBC 模型中诱导显着的生存益处。因此，靶向整合素 αvβ6-TGFβ-SOX4 通路为 TNBC 和其他高度侵袭性的人类上皮来源癌症提供了治疗机会。