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Bystander Expression of Atypical Chemokine Receptor 2 Protects T Cells from Chemoattraction Towards Cancer-Associated Fibroblasts

Overview
Journal Eur J Immunol
Date 2025 Feb 11
PMID 39931761
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Abstract

Atypical chemokine receptors (ACKRs) are a subclass of chemokine receptors that internalise and degrade chemokines instead of eliciting chemotaxis. Scavenging by ACKRs reduces the local bioavailability of chemokines and can thus reshape chemokine gradients that direct leukocyte trafficking during inflammation and anticancer responses. In pancreatic ductal adenocarcinoma (PDAC), chemokine axes, such as CXCL12-CXCR4, are co-opted by cancer-associated fibroblasts (CAFs) for tumour growth and escape, and immunosuppression. Here, we explore the use of ACKRs to reshape chemokine gradients within the PDAC tumour microenvironment. ACKR2, previously only known to scavenge inflammatory CC chemokines, was recently shown to be able to interact with CXCL10 and CXCL14. Here, using a chemokine binding assay and cytometric bead arrays, we reveal that ACKR2 scavenges additional CXC chemokines CXCL12 and CXCL1. ACKR2 scavenges CXCL12 with reduced efficiency compared to ACKR3, previously reported to bind CXCL12. Finally, we demonstrate that the overexpression of ACKR2 on bystander cells protects primary murine cytotoxic T lymphocytes from PDAC CAF-mediated chemoattraction. These findings reveal new CXC chemokine ligands of ACKR2 and indicate that ACKR overexpression may protect T cells from misdirection by CAFs.

References
1.
Nevala-Plagemann C, Hidalgo M, Garrido-Laguna I . From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer. Nat Rev Clin Oncol. 2019; 17(2):108-123. DOI: 10.1038/s41571-019-0281-6. View

2.
Feig C, Jones J, Kraman M, Wells R, Deonarine A, Chan D . Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013; 110(50):20212-7. PMC: 3864274. DOI: 10.1073/pnas.1320318110. View

3.
Overton W . Modified histogram subtraction technique for analysis of flow cytometry data. Cytometry. 1988; 9(6):619-26. DOI: 10.1002/cyto.990090617. View

4.
Hingorani S, Wang L, Multani A, Combs C, Deramaudt T, Hruban R . Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005; 7(5):469-83. DOI: 10.1016/j.ccr.2005.04.023. View

5.
Shabgah A, Jadidi-Niaragh F, Mohammadi H, Ebrahimzadeh F, Oveisee M, Jahanara A . The Role of Atypical Chemokine Receptor D6 (ACKR2) in Physiological and Pathological Conditions; Friend, Foe, or Both?. Front Immunol. 2022; 13:861931. PMC: 9168005. DOI: 10.3389/fimmu.2022.861931. View