Taner Hülya F, Gong Wang, Fitzsimonds Zackary R, Li Zaiye, Wu Yuesong, He Yumin, Okuyama Kohei, Cheng Wanqing, Kuczura Jung, Rajesh Sashider, Manousidaki Andriana, Feng Shuo, Lee Miki, Nör Felipe, Lanzel Emily, Demehri Shadmehr, Polverini Peter J, Nör Jacques E, Wang Thomas D, Que Jianwen, Wen Haitao, Xie Yuying, Moon James J, Lei Yu Leo
Oral Health Sciences DDS/PhD Program, University of Michigan School of Dentistry, Ann Arbor, MI 48105, USA.
Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
bioRxiv. 2024 Dec 10:2024.12.06.626475. doi: 10.1101/2024.12.06.626475.
Squamous cell carcinomas (SCC) are often preceded by potentially malignant precursor lesions, most of which remain benign. The terminal exhaustion phenotypes of effector T-cells and the accumulation of myeloid-derived suppressor cells (MDSC) have been thoroughly characterized in established SCC. However, it is unclear what precancerous lesions harbor a bona fide high risk for malignant transformation and how precancerous epithelial dysplasia drives the immune system to the point of no return. Here we show that expression of SRY-box transcription factor 2 (SOX2) in precancerous lesions imparts an irreversible risk that recruits suppressive myeloid cells by promoting the release of CCL2. We developed a unique genetically engineered mouse model (GEMM) to recapitulate the malignant transformation of epithelial dysplasia to SCC in the oral mucosa with high histologic and phenotypic fidelity. Using a combination of longitudinal human specimens and the Sox2-GEMM, we found that the myeloid cells in precancerous epithelial dysplasia exhibit a distinctive dichotomous profile featuring high levels of IL-1α-SLC2A1 and low levels of type-I interferon (IFN-I) signatures, which occurs before SCC emerges histologically. Brief priming of myeloid cells with IL-1α desensitizes them to IFN-I agonists and makes myeloid-derived suppressor cells (MDSC) even more suppressive of T-cell activation. Mechanistically, IL-1 activation represses the expression of DHHC3/7 enzymes, which are responsible for the palmitoylation of stimulator of interferon genes (STING). Early blockade of IL1 signaling using pharmacologic and genetic approaches similarly reduces MDSC and SLC2A1 myeloid cells, suppresses epithelial dysplasia transformation, and extends survival. This work establishes a previously unrecognized SOX2-CCL2-IL1 pathway that leads to irreversible immune escape when precancerous epithelial lesions transform.
鳞状细胞癌（SCC）通常由潜在恶性的前驱病变发展而来，其中大多数病变仍保持良性。效应T细胞的终末耗竭表型以及髓系来源抑制细胞（MDSC）的积累在已确诊的SCC中已有充分描述。然而，尚不清楚哪些癌前病变具有真正的恶性转化高风险，以及癌前上皮发育异常如何将免疫系统推向不可逆转的境地。在此，我们表明癌前病变中SRY盒转录因子2（SOX2）的表达赋予了一种不可逆的风险，即通过促进CCL2的释放来募集抑制性髓系细胞。我们开发了一种独特的基因工程小鼠模型（GEMM），以高度的组织学和表型保真度重现口腔黏膜上皮发育异常向SCC的恶性转化。通过结合纵向人类标本和Sox2-GEMM，我们发现癌前上皮发育异常中的髓系细胞呈现出一种独特的二分特征，即高水平的IL-1α-SLC2A1和低水平的I型干扰素（IFN-I）特征，这一特征在SCC组织学出现之前就已出现。用IL-1α短暂刺激髓系细胞会使其对IFN-I激动剂脱敏，并使髓系来源抑制细胞（MDSC）对T细胞激活的抑制作用更强。从机制上讲，IL-1激活会抑制DHHC3/7酶的表达，这些酶负责干扰素基因刺激物（STING）的棕榈酰化。使用药理学和遗传学方法早期阻断IL1信号通路同样会减少MDSC和SLC2A1髓系细胞，抑制上皮发育异常转化，并延长生存期。这项工作建立了一条先前未被认识的SOX2-CCL2-IL1通路，该通路在癌前上皮病变转化时导致不可逆的免疫逃逸。
