■人类染色体3q26-29的扩增,其编码p63家族的其他同种型中的癌蛋白ΔNp63,是多种组织起源的鳞状细胞癌(SCC)的常见特征。随着ΔNp63的过表达,原癌基因的激活,RAS,无论是通过过表达还是致癌突变,在许多癌症中经常观察到。在这项研究中,对癌症基因组图谱(TCGA)转录组数据的分析表明,TP63mRNA的表达,特别是ΔNp63同工型,在晚期头颈部鳞状细胞癌(HNSCC)中,HRAS显着升高,提示病理意义。然而,共同过表达的ΔNp63和HRAS如何影响免疫抑制肿瘤微环境(TME)尚不完全了解。
■这里,我们使用逆转录病毒介导的过表达ΔNp63α和组成型激活的HRAS(v-rasHaG12R)的原代角质形成细胞建立并表征了免疫活性小鼠模型,以评估这些癌基因在免疫TME中的作用。
■在这个模型中,表达v-rasHa和ΔNp63α水平升高的野生型同系角质形成细胞的原位移植在同系宿主中始终产生癌,而单独表达v-rasHa的细胞主要产生乳头状瘤。我们发现多形核(PMN)骨髓细胞,实验证实是免疫抑制的,因此代表骨髓来源的抑制细胞(PMN-MDSC),在表达ΔNp63α/v-rasHa的角质形成细胞原位移植后早期出现的癌的TME中被显着招募。与v-rasHa引发的肿瘤相比,ΔNp63α/v-rasHa驱动的癌表达更高水平的趋化因子与MDSCs的募集有关,在ΔNp63α/HRAS驱动的癌与免疫抑制性TME的发展之间提供了迄今为止未描述的联系。
■这些结果支持利用具有恶性肿瘤特定基因组驱动因素的遗传致癌模型来研究局部免疫抑制发展的潜在机制。
Amplification of human chromosome 3q26-29, which encodes oncoprotein ΔNp63 among other isoforms of the p63 family, is a feature common to
squamous cell carcinomas (SCCs) of multiple tissue origins. Along with overexpression of ΔNp63, activation of the protooncogene, RAS, whether by overexpression or oncogenic mutation, is frequently observed in many cancers. In this study, analysis of transcriptome data from The Cancer Genome Atlas (TCGA) demonstrated that expression of TP63 mRNA, particularly ΔNp63 isoforms, and HRAS are significantly elevated in advanced
squamous cell carcinomas of the head and neck (HNSCCs), suggesting pathological significance. However, how co-overexpressed ΔNp63 and HRAS affect the immunosuppressive tumor microenvironment (TME) is incompletely understood.
Here, we established and characterized an immune competent mouse model using primary keratinocytes with retroviral-mediated overexpression of ΔNp63α and constitutively activated HRAS (v-rasHa G12R) to evaluate the role of these oncogenes in the immune TME.
In this model, orthotopic grafting of wildtype syngeneic keratinocytes expressing both v-rasHa and elevated levels of ΔNp63α consistently yield carcinomas in syngeneic hosts, while cells expressing v-rasHa alone yield predominantly papillomas. We found that polymorphonuclear (PMN) myeloid cells, experimentally validated to be immunosuppressive and thus representing myeloid-derived suppressor cells (PMN-MDSCs), were significantly recruited into the TME of carcinomas arising early following orthotopic grafting of ΔNp63α/v-rasHa-expressing keratinocytes. ΔNp63α/v-rasHa-driven carcinomas expressed higher levels of chemokines implicated in recruitment of MDSCs compared to v-rasHa-initiated tumors, providing a heretofore undescribed link between ΔNp63α/HRAS-driven carcinomas and the development of an immunosuppressive TME.
These results support the utilization of a genetic carcinogenesis model harboring specific genomic drivers of malignancy to study mechanisms underlying the development of local immunosuppression.