Cxcr3 promotes protection from colorectal cancer liver metastasis by driving NK cell infiltration and plasticity
Eleonora Russo, Chiara D’Aquino, Chiara Di Censo, Mattia Laffranchi, Luana Tomaipitinca, Valerio Licursi, Stefano Garofalo, Johann Promeuschel, Giovanna Peruzzi, Francesca Sozio, Anna Kaffke, Cecilia Garlanda, Ulf Panzer, Cristina Limatola, Christian A.J. Vosshenrich, Silvano Sozzani, Giuseppe Sciumè, Angela Santoni, Giovanni Bernardini
Eleonora Russo, Chiara D’Aquino, Chiara Di Censo, Mattia Laffranchi, Luana Tomaipitinca, Valerio Licursi, Stefano Garofalo, Johann Promeuschel, Giovanna Peruzzi, Francesca Sozio, Anna Kaffke, Cecilia Garlanda, Ulf Panzer, Cristina Limatola, Christian A.J. Vosshenrich, Silvano Sozzani, Giuseppe Sciumè, Angela Santoni, Giovanni Bernardini
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Research Article Immunology Oncology

Cxcr3 promotes protection from colorectal cancer liver metastasis by driving NK cell infiltration and plasticity

Abstract

The antimetastatic activity of NK cells is well established in several cancer types, but the mechanisms underlying NK cell metastasis infiltration and acquisition of antitumor characteristics remain unclear. Herein, we investigated the cellular and molecular factors required to facilitate the generation of an ILC1-like CD49a+ NK cell population within the liver metastasis (LM) environment of colorectal cancer (CRC). We show that CD49a+ NK cells had the highest cytotoxic capacity among metastasis-infiltrating NK cells in the MC38 mouse model. Furthermore, the chemokine receptor CXCR3 promoted CD49a+ NK cell accumulation and persistence in metastasis where NK cells colocalize with macrophages in CXCL9- and CXCL10-rich areas. By mining a published scRNA-seq dataset of a cohort of patients with CRC who were treatment naive, we confirmed the accumulation of CXCR3+NK cells in metastatic samples. Conditional deletion of Cxcr3 in NKp46+ cells and antibody-mediated depletion of metastasis-associated macrophages impaired CD49a+NK cell development, indicating that CXCR3 and macrophages contribute to efficient NK cell localization and polarization in LM. Conversely, CXCR3neg NK cells maintained a CD49a– phenotype in metastasis with reduced parenchymal infiltration and tumor killing capacity. Furthermore, CD49a+ NK cell accumulation was impaired in an independent SL4-induced CRC metastasis model, which fails to accumulate CXCL9+ macrophages. Together, our results highlight a role for CXCR3/ligand axis in promoting macrophage-dependent NK cell accumulation and functional sustenance in CRC LM.

Authors

Eleonora Russo, Chiara D’Aquino, Chiara Di Censo, Mattia Laffranchi, Luana Tomaipitinca, Valerio Licursi, Stefano Garofalo, Johann Promeuschel, Giovanna Peruzzi, Francesca Sozio, Anna Kaffke, Cecilia Garlanda, Ulf Panzer, Cristina Limatola, Christian A.J. Vosshenrich, Silvano Sozzani, Giuseppe Sciumè, Angela Santoni, Giovanni Bernardini

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Figure 6

F4/80hi MAMs from MC38 but not SL4-induced metastasis include subsets expressing CXCL9 and TGF-β1.

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F4/80hi MAMs from MC38 but not SL4-induced metastasis include subsets ex...
(A) Representative FACS plots of CXCL9 expression on MHCII+ (red) or MHCII– (blue) F4/80hi macrophages in LM. Grey, isotype control (IC) staining. Histogram graph shows mean frequency ± SEM of CXCL9+ cells among MHCII+ or MHC-II– F4/80hi macrophages in MC38-injected mice (****P < 0.0001, 2-tailed Student’s t test). (B) Comparison of F4/80int and F4/80hi MAM mean frequency ± SEM between MC38-injected and SL4-injected mice (***P = 0.0002, 1-way ANOVA). (C) Mean frequency ± SEM of MHCII+ or MHCII– cells among F4/80hi MAMs in MC38- and SL4-induced LM (n > 9, *P = 0.04, **P = 0.001, 1-way ANOVA). (D) Comparison of CXCL9 gMFI and of frequency of LAP-1+ cells on MHCII+ or MHCII–F4/80hi macrophages in MC38- or SL4-injected mice. Mean ± SEM of at least 7 mice per group in 2 independent experiments (gMFI *P = 0.029, LAP-1 ***P = 0.0003, 1-way ANOVA). (E) Correlation between frequency of CD49a+ or CD49a– NK cells and matched MHCII+CXCL9+F4/80hi populations among CD45+ cells in LM from MC38-injected mice. Simple linear regression of correlation and Pearson correlation coefficient (R2) are shown (CD49a+ NK P = 0.02, CD49a– NK P = 0.62). (F) Immunofluorescence staining of liver metastasis: in blue DAPI staining for nuclei, in red F4/80, in green CXCL9/CXCL10 and in white NKp46. Top (original magnification, ×20), dotted line indicates tumor margin. Bottom, images at original magnification, ×63, with corresponding insets.