YTHDF2 Orchestrates Tumor-associated Macrophage Reprogramming and Controls Antitumor Immunity Through CD8 T Cells

Overview

Journal Nat Immunol

Date 2023 Jan 19

PMID 36658237

Authors

Shoubao Ma

Baofa Sun

Songqi Duan

JingJing Han

Tasha Barr

Jianying Zhang

Marc B Bissonnette

Marcin Kortylewski

Chuan He

Jianjun Chen

Michael A Caligiuri

Jianhua Yu

Affiliations

Soon will be listed here.

Abstract

Despite tumor-associated macrophages (TAMs) playing a key role in shaping the tumor microenvironment (TME), the mechanisms by which TAMs influence the TME and contribute to cancer progression remain unclear. Here, we show that the N-methyladenosine reader YTHDF2 regulates the antitumor functions of TAMs. YTHDF2 deficiency in TAMs suppressed tumor growth by reprogramming TAMs toward an antitumoral phenotype and increasing their antigen cross-presentation ability, which in turn enhanced CD8 T cell-mediated antitumor immunity. YTHDF2 deficiency facilitated the reprogramming of TAMs by targeting interferon-γ-STAT1 signaling. The expression of YTHDF2 in TAMs was regulated by interleukin-10-STAT3 signaling. Selectively targeting YTHDF2 in TAMs using a Toll-like receptor 9 agonist-conjugated small interfering RNA reprogrammed TAMs toward an antitumoral phenotype, restrained tumor growth and enhanced the efficacy of PD-L1 antibody therapy. Collectively, our findings describe the role of YTHDF2 in orchestrating TAMs and suggest that YTHDF2 inhibition is an effective approach to enhance cancer immunotherapy.

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