Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, MN 55118, USA.
Cell Rep. 2019 Sep 17;28(12):3092-3104.e5. doi: 10.1016/j.celrep.2019.08.038.
The immune system adapts to constitutive antigens to preserve self-tolerance, which is a major barrier for anti-tumor immunity. Antigen-specific reversal of tolerance constitutes a major goal to spur therapeutic applications. Here, we show that robust, iterative, systemic stimulation targeting tissue-specific antigens in the context of acute infections reverses established CD8 T cell tolerance to self, including in T cells that survive negative selection. This strategy results in large numbers of circulating and resident memory self-specific CD8 T cells that are widely distributed and can be co-opted to control established malignancies bearing self-antigen without concomitant autoimmunity. Targeted expansion of both self- and tumor neoantigen-specific T cells acts synergistically to boost anti-tumor immunity and elicits protection against aggressive melanoma. Our findings demonstrate that T cell tolerance can be re-adapted to responsiveness through robust antigenic exposure, generating self-specific CD8 T cells that can be used for cancer treatment.
免疫系统适应组成性抗原以保持自身耐受，这是抗肿瘤免疫的主要障碍。针对自身抗原特异性的耐受逆转是刺激治疗应用的主要目标。在这里，我们表明，在急性感染的情况下，针对组织特异性抗原的强大、迭代、系统性刺激可逆转已建立的 CD8 T 细胞对自身的耐受，包括在经历负选择后存活的 T 细胞中。这种策略导致大量循环和驻留记忆自身特异性 CD8 T 细胞广泛分布，并可被招募来控制具有自身抗原的已建立的恶性肿瘤而不伴发自身免疫。靶向扩增自身和肿瘤新抗原特异性 T 细胞协同作用以增强抗肿瘤免疫，并引发对侵袭性黑色素瘤的保护。我们的研究结果表明，通过强大的抗原暴露，T 细胞耐受可以重新适应反应性，从而产生可用于癌症治疗的自身特异性 CD8 T 细胞。
