Applications of Single-Cell Omics to Dissect Tumor Microenvironment.

Tingting Guo,Weimin Li,Xuyu Cai

doi:10.3389/fgene.2020.548719

Abstract

The recent technical and computational advances in single-cell sequencing technologies have significantly broaden our toolkit to study tumor microenvironment (TME) directly from human specimens. The TME is the complex and dynamic ecosystem composed of multiple cell types, including tumor cells, immune cells, stromal cells, endothelial cells, and other non-cellular components such as the extracellular matrix and secreted signaling molecules. The great success on immune checkpoint blockade therapy has highlighted the importance of TME on anti-tumor immunity and has made it a prime target for further immunotherapy strategies. Applications of single-cell transcriptomics on studying TME has yielded unprecedented resolution of the cellular and molecular complexity of the TME, accelerating our understanding of the heterogeneity, plasticity, and complex cross-interaction between different cell types within the TME. In this review, we discuss the recent advances by single-cell sequencing on understanding the diversity of TME and its functional impact on tumor progression and immunotherapy response driven by single-cell sequencing. We primarily focus on the major immune cell types infiltrated in the human TME, including T cells, dendritic cells, and macrophages. We further discuss the limitations of the existing methodologies and the prospects on future studies utilizing single-cell multi-omics technologies. Since immune cells undergo continuous activation and differentiation within the TME in response to various environmental cues, we highlight the importance of integrating multimodal datasets to enable retrospective lineage tracing and epigenetic profiling of the tumor infiltrating immune cells. These novel technologies enable better characterization of the developmental lineages and differentiation states that are critical for the understanding of the underlying mechanisms driving the functional diversity of immune cells within the TME. We envision that with the continued accumulation of single-cell omics datasets, single-cell sequencing will become an indispensable aspect of the immune-oncology experimental toolkit. It will continue to drive the scientific innovations in precision immunotherapy and will be ultimately adopted by routine clinical practice in the foreseeable future.

Highlights

A tumor grows within a highly complex and dynamic local environment composed of immune cells, stromal cells, endothelial cells, as well as other non-cellular components such as secreted cytokines, chemokines and extracellular matrix (ECM)
We will discuss the recent advances on understanding the diversity of tumor microenvironment (TME) and its functional impact on tumor progression and immunotherapy response driven by single-cell sequencing, with the primary focus on the major immune cell types identified within the TME
Identified overlapping immune checkpoint blockade (ICB) resistance program and post-ICB treatment program expressed by malignant cells: associated with T cell exclusion, down-regulation of antigen presenting cells (APCs) and IFN-g pathway

Summary

INTRODUCTION

A tumor grows within a highly complex and dynamic local environment composed of immune cells, stromal cells, endothelial cells, as well as other non-cellular components such as secreted cytokines, chemokines and extracellular matrix (ECM) This complex ecosystem is collectively termed as the tumor microenvironment (TME), characterized by its profound heterogeneity, plasticity, and complex cross-interaction (Fridman et al, 2017). With the continued accumulation of single-cell transcriptomics datasets and further extension to single-cell genomics, epigenomics and proteomics, we are geared to resolve the cellular composition and functional states of immune cells, and the developmental history, regulatory network and cellular interactions of tumor and immune cells Such increasing knowledge of the TME will pave the way for future precision immunotherapy through the establishment of connection between the TME within each patient’s tumor and the corresponding response to immunotherapy, and facilitate the design of optimal therapeutic strategies tailored to each patient. Multiple scRNA-seq studies have demonstrated that intratumoral cytotoxic CD8+ T cells are predominantly in the dysfunctional and exhausted state, characterized by their lack of classical effector cytokine secretion

Literature

Major conclusion

Method

CONCLUSION