ACKR4 restrains antitumor immunity by regulating CCL21

Whyte, Carly E.; Osman, Maleika; Kara, Elodie; Abbott, Caitlin; Foeng, Jade; McKenzie, Duncan R.; Fenix, Kevin; Harata-Lee, Yuka; Foyle, Kerrie L; Boyle, Sarah T.; Kochetkova, Marina; Aguilera, Amelia Roman; Hou, Jiajie; Li, Xian-Yang; Armstrong, Mark; Pederson, Stephen; Comerford, Iain; Smyth, Mark J.; McColl, Shaun R.

doi:10.1084/jem.20190634

Cited by 29 publications

(32 citation statements)

References 57 publications

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“…Recently, it was shown that the atypical chemokine receptor ACKR4 restrains antitumor immunity by decreasing intratumor CCL21. Deletion of ACKR4 in mice resulted in increased intratumor CCL21, retention of CD103+ dendritic cells, and an increase in CD8+ T-lymphocytes, which inhibited tumor growth (12).…”

Section: Chemokine Cues For Lymph Node Homing/disseminationmentioning

confidence: 99%

Lymphatic Vessels in Tumor Dissemination versus Immunotherapy

Vaahtomeri

Alitalo

2020

Cancer Research

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During the growth of various cancers, primary tumors can escape antitumor immune responses of their host and eventually disseminate into distant organs. Peritumoral lymphatic vessels connect the primary tumor to lymph nodes, facilitating tumor entry into lymph nodes, systemic circulation, and metastasis. Lymph node metastases that occur frequently provide sites of tumor cell spread, whereas tumor antigen transfer into and presentation in tumor-draining lymph nodes induce activation of tumor-specific T-lymphocyte responses that can result in cytolytic targeting of the tumor. Here, we discuss the recently emerged controversial role of the lymphatic vessels in tumor dissemination and cancer immunotherapy.

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Section: Chemokine Cues For Lymph Node Homing/disseminationmentioning

confidence: 99%

Lymphatic Vessels in Tumor Dissemination versus Immunotherapy

Vaahtomeri

Alitalo

2020

Cancer Research

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“…6,10 ACKR4 is best known for its role in shaping the gradient of CCL19 and CCL21 for CCR7-expressing DCs in the subcapsular sinuses of lymph nodes during the initiation phase of the adaptive immune response. 11,12 ACKR4 is also involved in antitumor immunity and modulates epithelial-mesenchymal transition and metastasis, [13][14][15] and studies with ACKR4-deficient mice in an EAE model also demonstrated the receptor implication in autoimmune diseases notably by F I G U R E 1 Systematic reassessment of human ACKR4 activation by chemokines using a highly sensitive -arrestin recruitment assay based on NanoBiT technology. (A) -arrestin-1 and -arrestin-2 recruitment to ACKR4 in response to all known human and 2 viral chemokines (100 nM).…”

Section: Brief Conclusive Reportmentioning

confidence: 99%

“…ACKR4 is best known for its role in shaping the gradient of CCL19 and CCL21 for CCR7‐expressing DCs in the subcapsular sinuses of lymph nodes during the initiation phase of the adaptive immune response 11,12 . ACKR4 is also involved in antitumor immunity and modulates epithelial‐mesenchymal transition and metastasis, 13–15 and studies with ACKR4‐deficient mice in an EAE model also demonstrated the receptor implication in autoimmune diseases notably by accelerated disease onset an more severe symptomes attributable to increased Th17 response 4,16 . Of note, 2 ACKR4‐defincient mouse strains (ACKR4 −/− and ACKR4 GFP/GFP ) are available and display distinct phenotypes.…”

Section: Brief Conclusive Reportmentioning

confidence: 99%

Systematic reassessment of chemokine-receptor pairings confirms CCL20 but not CXCL13 and extends the spectrum of ACKR4 agonists to CCL22

Meyrath

Reynders

Uchański

et al. 2020

Journal of Leukocyte Biology

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Atypical chemokine receptors (ACKRs) have emerged as important regulators or scavengers of homeostatic and inflammatory chemokines. Among these atypical receptors, ACKR4 is reported to bind the homeostatic chemokines CCL19, CCL21, CCL25 and CXCL13. In a recent study by Matti et al., the authors show that ACKR4 is also a receptor for CCL20, previously established to bind to CCR6 only. They provide convincing evidence that, just as for its other chemokine ligands, ACKR4 rapidly internalizes CCL20 both in vitro and in vivo. Independently of this discovery, we undertook a screening program aiming at reassessing the activity of the 43 human chemokines toward ACKR4 using a highly sensitive-arrestin recruitment assay. This systematic analysis confirmed CCL20 as a new agonist ligand for ACKR4 in addition to CCL19, CCL21, and CCL25. Furthermore, CCL22, which plays an important role in both homeostasis and inflammatory responses, and is known as a ligand for CCR4 and ACKR2 was found to also act as a potent partial agonist of ACKR4. In contrast, agonist activity of CXCL13 toward ACKR4 was disproved. This independent wide-range systematic study confirms the pairing of CCL20 with ACKR4 newly discovered by Matti and co-authors, and further refines the spectrum of chemokines activating ACKR4.

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“…KIAA1549 belongs to the UPF0606 family and is related to oncogenic MAPK signaling [24]. Atypical chemokine receptor 4 (ACKR4), which is a receptor for C-C type chemokines, has been shown to bind T cells and dendritic cell-activated chemokines and plays a signi cant role in controlling the migration of immune and cancer cells [25]. These ndings indicated that a number of mRNAs have changed during the peri-operative period that may play a role in the development of CRC.…”

Section: Discussionmentioning

confidence: 99%

Dynamic plasma extracellular vesicle long RNA profiling changes during the peri-operative period

Hua

Shen

et al. 2020

Preprint

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Background: Surgery remains the most important treatment strategy for solid tumors, such as colorectal cancer (CRC); However, a number of studies have suggested that surgical stress contributes to tumor recurrence or distant metastases. Extracellular vesicles (EVs), which contain a rich variety of RNAs with specialized functions and clinical applications, have been shown to be an indicator for diagnosis and prognosis of cancers. The effect of surgical stress on the landscape and characteristics of EV long RNA (exLR) in human blood, however, remains largely unknown.Methods: We present an optimized strategy for exLR sequencing (exLR-seq) the plasma from three patients with CRC at 4 time points (before surgery [T0], after extubation [T1], 1 day after surgery [T2], and 3 days after surgery [T4]). The “Limma” R package was used to evaluate the dynamic changes of mRNAs and long non-coding (lnc)RNAs from EVs. We also constructed a protein–protein interaction (PPI) network of hub genes and predicted biological processes, cellular components, and molecular functions of gene ontology (GO) functional analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Results: We observed a sufficient number of exLRs, including 12,924 mRNAs and 2196 lncRNAs. Both mRNAs and lncRNAs underwent dynamic changes during the peri-operative period. Compared with T0, there were 110 mRNAs differentially expressed after extubation, 60 differentially expressed genes（DEGs）1 day after surgery, and 50 DEGs 3 days after surgery. A total of 11 genes changed at all 3 time points and were related to regulation of the membrane potential, receptor complex, and passive transmembrane transporter activity. In addition, 22 lncRNAs were differentially expressed after extubation (T1). Nineteen lncRNAs were differentially expressed between T0 and T2, and 38 lncRNAs were differentially expressed between T0 and T3. In addition, we found that only 3 lncRNAs changed at 3 time points. Interestingly, blood exLRs reflected the tissue origins and relative fractions of different immune cell types. EVs from CD8+ T，CD4+ memory T, and NK cells decreased after surgery and the absolute quality of EVs from immune cells decreased as well. Conclusion: In summary, this study demonstrated abundant exLRs in human plasma and the dynamic changes of these exLRs and exLRs originating from CD8+ T and CD4+ memory T cells were reduced during the peri-operative period.

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ACKR4 restrains antitumor immunity by regulating CCL21

Cited by 29 publications

References 57 publications

Lymphatic Vessels in Tumor Dissemination versus Immunotherapy

Lymphatic Vessels in Tumor Dissemination versus Immunotherapy

Systematic reassessment of chemokine-receptor pairings confirms CCL20 but not CXCL13 and extends the spectrum of ACKR4 agonists to CCL22

Dynamic plasma extracellular vesicle long RNA profiling changes during the peri-operative period

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