Loss of the Intracellular Enzyme QPCTL Limits Chemokine Function and Reshapes Myeloid Infiltration to Augment Tumor Immunity

Overview

Journal Nat Immunol

Date 2022 Mar 22

PMID 35314846

Authors

Rosa Barreira da Silva

Ricardo M Leitao

Ximo Pechuan-Jorge

Scott Werneke

Jason Oeh

Vincent Javinal

Yingyun Wang

Wilson Phung

Christine Everett

Jim Nonomiya

David Arnott

Cheng Lu

Yi-Chun Hsiao

James T Koerber

Isidro Hotzel

James Ziai

Zora Modrusan

Thomas H Pillow

Merone Roose-Girma

Jill M Schartner

Mark Merchant

Sascha Rutz

Celine Eidenschenk

Ira Mellman

Matthew L Albert

Affiliations

Soon will be listed here.

Abstract

Tumor-associated macrophages are composed of distinct populations arising from monocytes or tissue macrophages, with a poorly understood link to disease pathogenesis. Here, we demonstrate that mouse monocyte migration was supported by glutaminyl-peptide cyclotransferase-like (QPCTL), an intracellular enzyme that mediates N-terminal modification of several substrates, including the monocyte chemoattractants CCL2 and CCL7, protecting them from proteolytic inactivation. Knockout of Qpctl disrupted monocyte homeostasis, attenuated tumor growth and reshaped myeloid cell infiltration, with loss of monocyte-derived populations with immunosuppressive and pro-angiogenic profiles. Antibody targeting of the receptor CSF1R, which more broadly eliminates tumor-associated macrophages, reversed tumor growth inhibition in Qpctl mice and prevented lymphocyte infiltration. Modulation of QPCTL synergized with anti-PD-L1 to expand CD8 T cells and limit tumor growth. QPCTL inhibition constitutes an effective approach for myeloid cell-targeted cancer immunotherapy.

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