PT  - JOURNAL ARTICLE
AU  - Rosa Barreira da Silva
AU  - Ricardo Leitão
AU  - Ximo Pechuan
AU  - Scott Werneke
AU  - Jason Oeh
AU  - Vincent Javinal
AU  - Yingyun Wang
AU  - Wilson Phung
AU  - Christine Everett
AU  - Jim Nonomiya
AU  - David Arnott
AU  - Cheng Lu
AU  - Yi-Chun Hsiao
AU  - James T. Koerber
AU  - Isidro Hotzel
AU  - James Ziai
AU  - Zora Modrusan
AU  - Thomas Pillow
AU  - Meron Roose-Girma
AU  - Jill M. Schartner
AU  - Mark Merchant
AU  - Sascha Rutz
AU  - Céline Eidenschenk
AU  - Ira Mellman
AU  - Matthew L. Albert
TI  - Loss of the intracellular enzyme QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity
AID  - 10.1101/2022.01.25.477769
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.25.477769
4099  - http://biorxiv.org/content/early/2022/01/28/2022.01.25.477769.short
4100  - http://biorxiv.org/content/early/2022/01/28/2022.01.25.477769.full
AB  - 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 enzyme that mediates N-terminal modification of several subtrates, 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 blockade of the receptor CSF1R, which more broadly eliminates tissue 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.Competing Interest StatementAll authors are current or former employees of Genentech.