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CCRL2 expression by specialized lung capillary endothelial cells controls NK-cell homing in lung cancer.

Francesca SozioTiziana SchioppaMattia LaffranchiValentina SalviNicola TamassiaFrancisco M Bianchetto-AguileraLaura TiberioRaffaella BonecchiDaniela BosisioMarc ParmentierBarbara BottazziRoberto LeoneEleonora RussoGiovanni BernardiniStefano GarofaloCristina LimatolaAngela GismondiGiuseppe SciumèAlberto MantovaniAnnalisa Del PreteSilvano Sozzani
Published in: Cancer immunology research (2023)
Patterns of receptors for chemotactic factors regulate the homing of leukocytes to tissues. Here we report that the CCRL2/chemerin/CMKLR1 axis represents a selective pathway for the homing of NK cells to the lung. C-C motif Chemokine Receptor-Like 2 (CCRL2) is a non-signaling seven-transmembrane domain receptor able to control lung tumor growth. CCRL2 constitutive or conditional endothelial cell targeted ablation, or deletion of its ligand chemerin, were found to promote tumor progression in a Kras/p53Flox lung cancer cell model. This phenotype was dependent on the reduced recruitment of CD27-CD11b+ mature NK cells. Other chemotactic receptors identified in lung-infiltrating NK cells by single-cell RNA sequencing (scRNA-seq), such as Cxcr3, Cx3cr1, and S1pr5, were found to be dispensable in the regulation of NK-cell infiltration of the lung and lung tumor growth. scRNA-seq identified CCRL2 as the hallmark of general alveolar lung capillary endothelial cells. CCRL2 expression was epigenetically regulated in lung endothelium and it was upregulated by the demethylating agent 5-aza-2'-deoxycytidine (5-Aza). In vivo administration of low doses of 5-Aza induced CCRL2 upregulation, increased recruitment of NK cells, and reduced lung tumor growth. These results identify CCRL2 as an NK-cell lung homing molecule that has the potential to be exploited to promote NK cell-mediated lung immune surveillance.
Keyphrases
  • nk cells
  • endothelial cells
  • single cell
  • public health
  • poor prognosis
  • high throughput
  • high glucose
  • cell proliferation
  • nitric oxide
  • oxidative stress
  • vascular endothelial growth factor
  • cancer therapy