Vile Richard, Pulido Jose, Chen Alex, Kendall Benjamin, Tonne Jason, Metko Muriel, Thompson Jill, Sangsuwannukul Thanich, Yerovi Maria Chiriboga, Diaz Rosa, Webb Mason, Huff Amanda, Moore Madelyn, Schuelke Matthew, Irshad Sheeba, Appleton Elizabeth, Melcher Alan
Mayo Clinic.
Johns Hopkins University.
Res Sq. 2024 Nov 15:rs.3.rs-5411393. doi: 10.21203/rs.3.rs-5411393/v1.
T cell immune tolerance is established in part through the activity of the Auto-immune Regulator (AIRE) transcription factor in the medullary Thymic Epithelial Cells (mTEC) of the thymus. AIRE induces expression of SELF peripheral tissue-specific antigens for presentation to naïve T cells to promote activation/deletion of potentially autoreactive T cells. We show, for the first time to our knowledge, that tumors mimic the role of AIRE in mTEC to evade immune rejection. Thus, by expressing a broad range of SELF epitopes against which minimal functional T cell reactivities exist because of thymic deletion, AIRE acts as a master controller of SELFNESS, effectively cloaking the tumor from T cell attack. Moreover, we describe a completely novel immunotherapy in which engineered changes in AIRE expression in tumor cells alters their profile of SELFNESS, exposing both AIRE-modified, and parental unmodified, tumor cells to T cell attack. Consistent with our studies, patient RNAseq shows expression of AIRE predicts response to immune therapies with a strong correlation between AIRE expression and markers of TCR signaling. Therefore, by re-setting the immunological SELFNESS of cancer cells, this novel AIRE-mediated immunotherapy 1). converts a highly tolerized T cell compartment into a heteroclitic tumor-reactive T cell population; 2) confers sensitivity to immune checkpoint blockade upon non-immunogenic tumors; 3). completely removes the need to identify potentially immunogenic tumor-associated antigens as targets for generation of CD8 and helper CD4 T cell responses; and 4) leads to potent T cell-mediated rejection of aggressive, immunologically cold, non-immunogenic tumors.
T细胞免疫耐受部分是通过自身免疫调节因子（AIRE）转录因子在胸腺髓质胸腺上皮细胞（mTEC）中的活性来建立的。AIRE诱导自身外周组织特异性抗原的表达，以呈递给幼稚T细胞，从而促进潜在自身反应性T细胞的激活/清除。据我们所知，我们首次表明肿瘤模仿了AIRE在mTEC中的作用以逃避免疫排斥。因此，通过表达广泛的自身表位，由于胸腺清除，针对这些表位存在最小的功能性T细胞反应性，AIRE充当自身性的主要控制器，有效地使肿瘤免受T细胞攻击。此外，我们描述了一种全新的免疫疗法，其中肿瘤细胞中AIRE表达的工程化改变改变了它们的自身性概况，使经AIRE修饰的肿瘤细胞和亲本未修饰的肿瘤细胞都暴露于T细胞攻击之下。与我们的研究一致，患者RNA测序显示AIRE的表达预测对免疫疗法的反应，AIRE表达与TCR信号标志物之间存在强相关性。因此，通过重新设定癌细胞的免疫自身性，这种新型的AIRE介导的免疫疗法1）. 将高度耐受的T细胞区室转化为具有异质性的肿瘤反应性T细胞群体；2）. 赋予非免疫原性肿瘤对免疫检查点阻断的敏感性；3）. 完全无需鉴定潜在的免疫原性肿瘤相关抗原作为产生CD8和辅助性CD4 T细胞反应的靶标；4）. 导致T细胞介导的对侵袭性、免疫冷性、非免疫原性肿瘤的有效排斥。
