Checkpoint immunotherapy is a major breakthrough for cancer treatment, yet its efficacy is often limited against many types of malignancies, including malignant mesothelioma. Considering that the immunotherapeutic efficacy depends on immunosurveillance, we sought to develop an active immunization method to break immune tolerance to tumor self-antigen. Here, we demonstrated that TWIST1, the basic helix-loop-helix transcription factor, was associated with human mesothelioma tumorigenesis and required for the invasion and metastasis of mesothelioma in the immune-competent murine AB1 model. When conventional TWIST1 vaccines were not effective in vivo, programmed cell death protein 1 (PD1)-based vaccination provided prophylactic control by inducing long-lasting TWIST1-specific T cell responses against both subcutaneous and metastatic mesothelioma lethal challenges. Furthermore, while CTLA-4 blockade alone did not show any immunotherapeutic efficacy against established mesothelioma, its combination with PD1-based vaccination resulted in 60% complete remission. Mechanistically, these functional T cells recognized a novel highly conserved immunodominant TWIST1 epitope, exhibited cytotoxic activity and long-term memory, and led to durable tumor regression and survival benefit against established AB1 mesothelioma and 4T1 breast cancer. We concluded that PD1-based vaccination controls mesothelioma by breaking immune tolerance to the tumor self-antigen TWIST1. Our results warrant clinical development of the PD1-based vaccination to enhance immunotherapy against a wide range of TWIST1-expressing tumors.

Checkpoint免疫疗法是癌症治疗的一项重大突破，但其功效通常仅限于针对多种类型的恶性肿瘤，包括恶性间皮瘤。考虑到免疫治疗效果取决于免疫监测，我们寻求开发一种主动免疫方法来打破对肿瘤自身抗原的免疫耐受性。在这里，我们证明了TWIST1，基本的螺旋-环-螺旋转录因子，与人类间皮瘤的肿瘤发生有关，并且是具有免疫功能的鼠AB1模型中间皮瘤的侵袭和转移所必需的。当常规TWIST1疫苗在体内无效时，基于程序性细胞死亡蛋白1（PD1）的疫苗接种通过诱导针对皮下和转移性间皮瘤致死性攻击的持久TWIST1特异性T细胞反应，提供了预防性控制。此外，虽然单独使用CTLA-4阻断剂对已建立的间皮瘤没有任何免疫治疗效果，但将其与基于PD1的疫苗接种相结合可实现60％的完全缓解。从机制上讲，这些功能性T细胞识别出新的高度保守的免疫优势TWIST1表位，表现出细胞毒活性和长期记忆，并导致持久的肿瘤消退和对已建立的AB1间皮瘤和4T1乳腺癌的生存益处。我们得出的结论是，基于PD1的疫苗接种可通过破坏对肿瘤自身抗原TWIST1的免疫耐受来控制间皮瘤。