Aberrant m6A mRNA methylation in intratumoral C1Q+ Macrophages directs the T cell exhaustion and limits anti-tumor immune response
Release date:
2021-04-17
Description:
T cell dysfunction is a major barrier limiting the efficacy of cancer immunotherapies. However, the extrinsic cues orchestrating T cell dysfunction remain elusive. Here, we show C1q+ tumor-associated macrophages (TAMs), characterized by a unique N6-methyadenosine methylation program, engage in crosstalk with tumor-infiltrating CD8+ T cells. Single-cell RNA sequencing reveals that macrophage-specific knockout of Mettl14, a component of the m6A 'writer' complex, drives CD8+ T cell differentiation along a dysfunctional trajectory, ultimately impairing the capacity of these CD8+ T cells to eliminate tumors. Supporting the clinical relevance of these insights, we show that the Mettl14-m6A levels are negatively correlated with dysfunctional-T-cell levels in patients with colorectal cancer. Our study demonstrates how an m6A methylation writer in TAMs regulates CD8+ T cell dysfunction within tumors.
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Organization: Beijing Institute of Genomics, Chinese Academy of Sciences
Submission date: 2021-04-17
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HRA000785.xlsx