Loss of the intracellular enzyme QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity

Barreira da Silva, R.; Leitao, R.; Pechuan, X.; Werneke, S.; Oeh, J.; Javinal, V.; Wang, Y.; Phung, W.; Everett, C.; Nonomiya, J.; Arnott, D.; Lu, C.; Hsiao, Y.-C.; Koerber, J. T.; Hotzel, I.; Ziai, J.; Modrusan, Z.; Pillow, T.; Roose-Girma, M.; Schartner, J. M.; Merchant, M.; Rutz, S.; Eidenschenk, C.; Mellman, I.; Albert, M.

doi:10.1101/2022.01.25.477769

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bioRxiv · 10.1101/2022.01.25.477769

Loss of the intracellular enzyme QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity

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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 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.

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Barreira da Silva, R., Leitao, R., Pechuan, X., Werneke, S., Oeh, J., Javinal, V., Wang, Y., Phung, W., Everett, C., Nonomiya, J., Arnott, D., Lu, C., Hsiao, Y.-C., Koerber, J. T., Hotzel, I., Ziai, J., Modrusan, Z., Pillow, T., Roose-Girma, M., Schartner, J. M., Merchant, M., Rutz, S., Eidenschenk, C., Mellman, I., Albert, M.. 2022-01-28. Loss of the intracellular enzyme QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity. https://doi.org/10.1101/2022.01.25.477769

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