Single-cell RNA Sequencing Demonstrates Inter-Patient Heterogeneity and Altered Tumor Microenvironment in Invasive and Intraductal Cribriform Prostate Cancer

ICC and IDC are aggressive histological subtypes of prostate cancer that are associated with progression to lethal disease. To delineate cancer cell intrinsic as well as tumor microenvironmental factors that contribute to ICC/IDC aggressiveness, this study examined paired ICC/IDC-enriched and benign-enriched prostate samples obtained from radical prostatectomy (RP) by scRNAseq, TCR sequencing and histology. ICC/IDC cancer cells had robust inter-patient heterogeneity but upregulated similar pathways (MYC and TNF via NF?B) and targets with potential for therapeutic intervention (PSMA and B7-H3). ICC/IDC was associated with increased neovasculature, and cancer foci were densely circumscribed by immunosuppressive CAF likely derived from APOD+ peri-epithelial fibroblast progenitors. The ICC/IDC TME had fewer and more dysfunctional T cells and increased M2 polarization of two macrophage subtypes compared to benign prostate. These findings support that ICC/IDC are hallmarked by several aggressive features that likely contribute to their association with lethal prostate cancer. Overall design: scRNA-seq (whole transcriptome and TCR) performed on paired ICC/IDC-enriched and benign-enriched prostate samples obtained from radical prostatectomy.

导管内癌（ICC）与浸润性导管癌（IDC）是前列腺癌的侵袭性组织学亚型，与致死性疾病进展密切相关。为阐明驱动ICC/IDC侵袭性的癌细胞内在因素与肿瘤微环境因素，本研究针对根治性前列腺切除术（RP）获取的配对ICC/IDC富集样本与良性前列腺富集样本，通过单细胞RNA测序（scRNAseq）、T细胞受体（TCR）测序及组织学分析开展检测。ICC/IDC癌细胞呈现显著的患者间异质性，但均上调了相似的通路（MYC及经核因子κB（NF-κB）激活的肿瘤坏死因子TNF通路）与具备治疗干预潜力的靶点（前列腺特异性膜抗原PSMA与B7-H3）。ICC/IDC与新生血管增多相关，癌灶被免疫抑制性癌相关成纤维细胞（CAF）紧密包裹，这类CAF大概率源自载脂蛋白D阳性（APOD+）的上皮周围成纤维细胞祖细胞。与良性前列腺组织相比，ICC/IDC的肿瘤微环境（TME）中T细胞数量更少且功能失调程度更高，且两种巨噬细胞亚型的M2型极化水平均有所升高。上述研究结果表明，ICC/IDC具备多项侵袭性特征，这些特征或可解释其与致死性前列腺癌的关联。实验整体设计：针对根治性前列腺切除术获取的配对ICC/IDC富集样本与良性前列腺富集样本，开展单细胞RNA测序（scRNA-seq，涵盖全转录组与T细胞受体测序）。