QPCTL regulates macrophage and monocyte abundance and inflammatory signatures in the tumor microenvironment. (31st December 2022)

• Record Type: Journal Article
• Authors: Bresser, Kaspar; Logtenberg, Meike E. W.; Toebes, Mireille; Proost, Natalie; Sprengers, Justin; Siteur, Bjorn; Boeije, Manon; Kroese, Lona J.; Schumacher, Ton N.
• Is Part Of: Oncoimmunology. Volume 11:Number 1(2022)
• Publication Date: 2022-12-31
• Subjects: QPCTL -- tumor micro-environment -- cancer-associated fibroblasts -- genetically modified mouse model; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2022.2049486
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: 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.