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Bystander Expression of Atypical Chemokine Receptor 2 Protects T Cells from Chemoattraction towards Cancer-Associated
Richard Tang1, Szun S Tay1, George Sharbeen2
1EMBL Australia, Single Molecule Science node, School of Biomedical Sciences, The University of New South Wales, Sydney, NSW, Australia.
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.
Insights
Atypical chemokine receptors (ACKRs) like ACKR2 can scavenge chemokines, including CXCL12, in pancreatic cancer. Overexpressing ACKR2 protects T cells from cancer-associated fibroblast attraction, aiding anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Atypical chemokine receptors (ACKRs) internalize chemokines, modulating leukocyte trafficking in inflammation and cancer.
- In pancreatic ductal adenocarcinoma (PDAC), cancer-associated fibroblasts (CAFs) exploit chemokine signaling for tumor progression.
- ACKR2 was known to scavenge CC chemokines and some CXC chemokines like CXCL10 and CXCL14.
Purpose of the Study:
- To investigate the role of ACKR2 in scavenging CXC chemokines within the PDAC tumor microenvironment.
- To determine if ACKR2 can scavenge CXCL12 and CXCL1.
- To assess the potential of ACKR2 to protect cytotoxic T lymphocytes from CAF-mediated chemoattraction.
Main Methods:
- Chemokine binding assays were used to test ACKR2's interaction with various chemokines.
- Cytometric bead arrays quantified chemokine levels.
- Murine cytotoxic T lymphocytes were used to evaluate ACKR2's protective effect against CAF chemoattraction.
Main Results:
- ACKR2 was confirmed to scavenge additional CXC chemokines, specifically CXCL12 and CXCL1.
- ACKR2 scavenges CXCL12, though less efficiently than ACKR3.
- Overexpression of ACKR2 on bystander cells protected cytotoxic T lymphocytes from PDAC CAF-driven chemoattraction.
Conclusions:
- ACKR2 interacts with and scavenges CXCL12 and CXCL1, expanding its known CXC chemokine ligand repertoire.
- ACKR2-mediated scavenging of chemokines can potentially protect anti-tumor T cells from misdirection by CAFs in PDAC.
- Targeting ACKR expression may represent a novel strategy to enhance anti-cancer immune responses in PDAC.
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