OncoImmunology (Dec 2022)

QPCTL regulates macrophage and monocyte abundance and inflammatory signatures in the tumor microenvironment

  • Kaspar Bresser,
  • Meike E. W. Logtenberg,
  • Mireille Toebes,
  • Natalie Proost,
  • Justin Sprengers,
  • Bjorn Siteur,
  • Manon Boeije,
  • Lona J. Kroese,
  • Ton N. Schumacher

DOI
https://doi.org/10.1080/2162402X.2022.2049486
Journal volume & issue
Vol. 11, no. 1

Abstract

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The enzyme glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyzes the formation of pyroglutamate residues at the NH2-terminus of proteins, thereby influencing their biological properties. A number of studies have implicated QPCTL in the regulation of chemokine stability. Furthermore, QPCTL activity has recently been shown to be critical for the formation of the high-affinity SIRPα binding site of the CD47 “don’t-eat-me” protein. Based on the latter data, interference with QPCTL activity —and hence CD47 maturation—may be proposed as a means to promote anti-tumor immunity. However, the pleiotropic activity of QPCTL makes it difficult to predict the effects of QPCTL inhibition on the tumor microenvironment (TME). Using a syngeneic mouse melanoma model, we demonstrate that QPCTL deficiency alters the intra-tumoral monocyte-to-macrophage ratio, results in a profound increase in the presence of pro-inflammatory cancer-associated fibroblasts (CAFs) relative to immunosuppressive TGF-β1-driven CAFs, and leads to an increased IFN and decreased TGF-β transcriptional response signature in tumor cells. Importantly, the functional relevance of the observed TME remodeling is demonstrated by the synergy between QPCTL deletion and anti PD-L1 therapy, sensitizing an otherwise refractory melanoma model to anti-checkpoint therapy. Collectively, these data provide support for the development of strategies to interfere with QPCTL activity as a means to promote tumor-specific immunity.

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