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

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.