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 8

Deletion of Cxcr3 in Ncr1+ ILCs impairs CD49a+ NK generation and accelerates metastasis formation.

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Deletion of Cxcr3 in Ncr1+ ILCs impairs CD49a+ NK generation and acceler...
(A) Cake plots show incidence of LM in Cxcr3fl/fl and Ncr1ΔCxcr3 mice 15 days p.i. 2 independent experiments were performed. (B) Top, representative pictures of metastatic livers and hematoxylin-eosin staining. Bottom, scatter plots show mean ± SEM of metastasis weight (gr) and number and quantification of liver section from Cxcr3fl/fl (grey) and Ncr1ΔCxcr3 (red) mice 20 days p.i. 3 independent experiments were performed (Met Weight *P = 0.012, no. metastases *P = 0.022, 2-tailed Student’s t test). (C) Representative contour plots of ILC1, CD49a+ NK and CD49a– NK cells in MFL and LM from Cxcr3fl/fl and Ncr1ΔCxcr3 mice. Numbers in plots correspond to frequency. Histograms show corresponding median frequency with 95% CI among NK1.1+ NKp46+ cells (ILC1 *P = 0.026, CD49a+ NK **P = 0.0015, 2-tailed Student’s t test to compare Cxcr3fl/fl and Ncr1ΔCxcr3 cell frequency). (D) Histogram plots show frequency of DCs, F4/80int and F4/80hi macrophages in MFL and LM of Cxcr3fl/fl and Ncr1ΔCxcr3 tumor-bearing mice among CD45+ cells. Data are presented as mean ± SEM. Three independent experiments were performed.