Multiomics characteristics of neurogenesis-related gene are dysregulated in tumor immune microenvironment

Ben Wang,Mengmeng Liu,Zhujie Ran,Yunsheng Ou,Hai Mou,Jie Li,Xin Li

doi:10.1038/s41525-021-00202-y

Abstract

The success of immunotherapy was overshadowed by its low response rate, and the hot or cold tumor microenvironment was reported to be responsible for it. However, due to the lack of an appropriate method, it is still a huge challenge for researchers to understand the molecular differences between hot and cold tumor microenvironments. Further research is needed to gain deeper insight into the molecular characteristics of the hot/cold tumor microenvironment. A large-scale clinical cohort and single-cell RNA-seq technology were used to identify the molecular characteristics of inflamed or noninflamed tumors. With single-cell RNA sequencing technology, we provided a novel method to dissect the tumor microenvironment into a hot/cold tumor microenvironment to help us understand the molecular differences between hot and cold tumor microenvironments. Compared with cold tumors, hot tumors highly expressed B cell-related genes, such as MS4A1 and CXCR5, neurogenesis-related miRNA such as MIR650, and immune molecule-related lncRNA such as MIR155HG and LINC00426. In cold tumors, the expression of genes related to multiple biological processes, such as the neural system, was significantly upregulated, and methylome analysis indicated that the promoter methylation level of genes related to neurogenesis was significantly reduced. Finally, we investigated the pan-cancer prognostic value of the cold/hot microenvironment and performed pharmacogenomic analysis to predict potential drugs that may have the potential to convert the cold microenvironment into a hot microenvironment. Our study reveals the multiomics characteristics of cold/hot microenvironments. These molecular characteristics may contribute to the understanding of immune exclusion and the development of microenvironment-targeted therapy.

Highlights

The recent clinical successes of immunotherapy, including immune checkpoint inhibitors and adoptive cell therapy, represent a turning point in cancer treatment[1,2]
Neuroendocrine-related molecular characteristics have been reported in some tumors, but little is known about how the tumor genome shapes it[16,47]
We found that neurogenesis-associated multiomics characteristics were significantly dysregulated between noninflamed and inflamed tumor microenvironments, which is interesting and complements previous reports

Summary

Introduction

The recent clinical successes of immunotherapy, including immune checkpoint inhibitors and adoptive cell therapy, represent a turning point in cancer treatment[1,2]. Clinical trials of anti-PD-1 for patients with melanoma have demonstrated substantial therapeutic responses. Despite these encouraging clinical results, only a fraction of patients can benefit from immunotherapy[3]. Recent studies suggest that the phenotype of the tumor microenvironment (TME) is a critical factor influencing the efficacy of immunotherapy. The inflammatory tumor microenvironment was characterized by rich infiltration of immune cells. These tumors are correlated with significant tumor regression when treated by immunotherapy[6,7,8,9,10]. Due to the lack of appropriate experimental methods, how different tumor cells shape their TME, thereby determining their response to therapy, remains a critical unsolved problem

Methods

Results

Conclusion