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Diverse intratumoral heterogeneity and immune microenvironment of two HPV-related cervical cancer types revealed by single cell transcriptomic profiling

ABSTRACT: Cervical squamous cell carcinoma (SCC) and adenocarcinoma (AD) are the main histological types of HPV-related cervical cancer (CC). However, reports on cell type-specific molecular difference between SCC and AD are scanty. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular differences between SCC and AD in tumor heterogeneity, and tumor microenvironment (TME). A total of 61,723 cells from three SCC and three AD patients, were collected and classified into nine cell types. The tumor cells between SCC and AD showed high intra- and inter-patient heterogeneity and functional diversity. Signaling pathways, such as epithelial-to-mesenchymal-transition (EMT), hypoxia and inflammatory response were up-regulated in SCC, while cell cycle-related signaling pathways were enriched in AD. SCC was associated with high infiltration of exhausted CD8 T cells, effector memory CD8 T cells, and NK cells, as well as tumor-associated macrophages (TAMs) with higher MHC-II biomarkers. AD exhibited high infiltration of naive CD8 T cell, Treg, tissue-resident T cells, cytotoxicity CD8 T cells as well as TAMs with regulation functions. In addition, we found that the majority of cancer-associated fibroblasts (CAFs) were derived from AD, and participated in inflammatory regulation, while CAFs in SCC showed similar functions to tumor cells, such as EMT and hypoxia. This study revealed the widespread reprogramming of multiple cell populations in SCC and AD , dissected the cellular heterogeneity and characteristics in TME, and proposed potential therapeutic strategy for anticancer treatment, such as targeted therapy and immunotherapy for CC.

ORGANISM(S): Homo sapiens (human)

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PROVIDER: S-BSST1035 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Background:Cellular heterogeneity within the tumor microenvironment is essential to tumorigenesis and tumor development. A high-resolution global view of the tumor-infiltrating immune and stromal cells in breast tumors is needed. Methods:xCell was used to create a cellular heterogeneity map of 64 cell types in 1,092 breast tumor and adjacent normal tissues. xCell digitally dissects tissue cellular heterogeneity based on gene expression. Integrated statistical analyses were then performed. Results:There were noticeable differences between the cell fractions in tumor tissues and normal tissues. Tumors displayed higher proportions of immune cells, including CD4+ Tem, CD8+ naïve T cells, and CD8+ Tcm compared with normal tissues. Immune inhibitory receptors (PD1, CTLA4, LAG3 and TIM3) were co-expressed on certain subtypes of T cells in breast tumors, and PD1 and CTLA4 were both positively correlated with CD8+ Tcm and CD8+ T cells. 28 cell types were significantly associated with overall survival in univariate analysis. CD4+ Tem, CD8+ Tcm, CD8+ T-cells, CD8+ naive T-cells, and B cells were positive prognostic factors but CD4+ naive T-cells were negative prognostic factors for breast cancer patients. TDRD6 and TTK are promising T cell and B cell targets for tumor vaccines. Endothelial cells and fibroblasts were significantly less prevalent in tumor tissues; astrocytes and mesangial cells were negatively correlated with the T stage. Mesangial cells and keratinocytes were found to be favorable prognostic factors and myocytes were negative prognostic factors. Five cell types were found to be independent prognostic factors and we used these to create a reliable prognostic model for breast cancer patients. Cellular heterogeneity was discovered among different breast cancer subtypes by Her2, ER, and PR status. Tri-negative patients had the highest fraction of immune cells while luminal type patients had the lowest. The various cells may have diverse or opposing roles in the prognosis of breast cancer patients. Conclusions:We created a uniquecellular map for the diverse heterogeneity of immune and stromal phenotypes within the breast tumor microenvironment. This map may lead to potential therapeutic targets and biomarkers with prognostic utility.

Project description:BackgroundPituitary neuroendocrine tumors (PitNETs) are one of the most common types of intracranial tumors. Currently, the cellular characteristics of normal pituitary and various other types of PitNETs are still not completely understood.MethodsWe performed single-cell RNA sequencing (scRNA-seq) on 4 normal samples and 24 PitNET samples for comprehensive bioinformatics analysis. Findings regarding the function of PBK in the aggressive tumor cells were validated by siRNA knockdown, overexpression, and transwell experiments.ResultsWe first constructed a reference cell atlas of the human pituitary. Subsequent scRNA-seq analysis of PitNET samples, representing major tumor subtypes, shed light on the intrinsic cellular heterogeneities of the tumor cells and tumor microenvironment (TME). We found that the expression of hormone-encoding genes defined the major variations of the PIT1-lineage tumor cell transcriptomic heterogeneities. A sub-population of TPIT-lineage tumor cells highly expressing GZMK suggested a novel subtype of corticotroph tumors. In immune cells, we found two clusters of tumor-associated macrophages, which were both highly enriched in PitNETs but with distinct functional characteristics. In PitNETs, the stress response pathway was significantly activated in T cells. While a majority of these tumors are benign, our study unveils a common existence of aggressive tumor cells in the studied samples, which highly express a set of malignant signature genes. The following functional experiments confirmed the oncogenic role of selected up-regulated genes. The over-expression of PBK could promote both tumor cell proliferation and migration, and it was also significantly associated with poor prognosis in PitNET patients.ConclusionsOur data and analysis manifested the basic cell types in the normal pituitary and inherent heterogeneity of PitNETs, identified several features of the tumor immune microenvironments, and found a novel epithelial cell sub-population with aggressive signatures across all the studied cases.

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Diverse intratumoral heterogeneity and immune microenvironment of two HPV-related cervical cancer types revealed by single cell transcriptomic profiling

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