Deletion of p53 and Hyper-Activation of PIK3CA in Keratin-15+ Stem Cells Lead to the Development of Spontaneous Squamous Cell Carcinoma.

Zhangguo Chen,Rachel A Woolaver,Christian D Young,Samantha M Y Chen,Bian Li,Tonya Brunetti,Xiao-Jing Wang,Alexandra L Krinsky,Jing H Wang,Xiaoguang Wang,Dexiang Gao,Andrew G Nicklawsky

doi:10.3390/ijms21186585

Zhangguo Chen, Rachel A Woolaver + Show 10 more

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https://doi.org/10.3390/ijms21186585

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Abstract

Squamous cell carcinoma (SCC) is the second commonest type of skin cancer, and SCCs make up about 90% of head and neck cancers (HNSCCs). HNSCCs harbor two frequent molecular alterations, namely, gain-of-function alterations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and loss-of-function mutations of tumor protein p53 (TP53). However, it remains poorly understood whether HNSCCs harboring different genetic alterations exhibit differential immune tumor microenvironments (TME). It also remains unknown whether PIK3CA hyperactivation and TP53 deletion can lead to SCC development spontaneously. Here, we analyzed the Cancer Genome Atlas (TCGA) datasets of HNSCCs and found that patients with both PIK3CA and TP53 alterations exhibited worse survival, significantly lower CD8 tumor infiltrating lymphocytes (TILs) and higher M0 macrophages than other controls. To better model human tumorigenesis, we deleted TP53 and constitutively activated PIK3CA in mouse keratin-15-expressing stem cells, which leads to the spontaneous development of multilineage tumors including SCCs, termed Keratin-15-p53-PIK3CA (KPPA) tumors. KPPA tumors were heavily infiltrated with myeloid-derived suppressor cells (MDSCs), with a drastically increased ratio of polymorphonuclear-MDSC (PMN-MDSC) versus monocytic-MDSC (M-MDSC). CD8 TILs expressed more PD-1 and reduced their polyfunctionality. Overall, we established a genetic model to mimic human HNSCC pathogenesis, manifested with an immunosuppressive TME, which may help further elucidate immune evasion mechanisms and develop more effective immunotherapies for HNSCCs.

Highlights

Head and neck cancers (HNC) are a heterogeneous group of tumors arising from the mucosal surfaces of the upper aerodigestive tract [1]
The Cancer Genome Atlas (TCGA) RNA-seq data and clinical data of head and neck squamous cell carcinomas (HNSCCs) cohorts were obtained from the cBioPortal
In analyzing the dataset of HNSCC patients (TCGA, PanCancer Atlas, n = 489 samples), we found that the patients with PIK3CA alterations, including amplification and gain, have a higher chance of harboring tumor protein p53 (TP53) mutations (Figure 1A)

Summary

Introduction

Head and neck cancers (HNC) are a heterogeneous group of tumors arising from the mucosal surfaces of the upper aerodigestive tract [1]. Some 90% of all HNCs are head and neck squamous cell carcinomas (HNSCCs) and HNSCCs are often associated with either carcinogens, such as alcohol and tobacco use, or oncogenic human papillomavirus (HPV) infection [2,3], thereby categorized as HPV(−) or HPV(+) HNSCCs. HNSCCs have been found to be diverse with a high rate of genetic heterogeneity, resulting in hyper-activation of oncogenes (e.g., PIK3CA and HRAS) and loss-of-function mutations in tumor suppressor genes (e.g., TP53, CASP8, and NOTCH1) [4,5]. Monoclonal antibodies (mAbs) that inhibit EGFR have been used for both HPV(−) and HPV(+) subtypes of HNSCCs; they were found to have limited efficacy and elicited resistance [10]

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