Russo Eleonora, D'Aquino Chiara, Di Censo Chiara, Laffranchi Mattia, Tomaipitinca Luana, Licursi Valerio, Garofalo Stefano, Promeuschel Johann, Peruzzi Giovanna, Sozio Francesca, Kaffke Anna, Garlanda Cecilia, Panzer Ulf, Limatola Cristina, Vosshenrich Christian Aj, Sozzani Silvano, Sciumè Giuseppe, Santoni Angela, Bernardini Giovanni
Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
Innate Immunity Unit, Institut Pasteur, Université Paris Cité, INSERM U1223, Paris, France.
J Clin Invest. 2025 Apr 1;135(11). doi: 10.1172/JCI184036. eCollection 2025 Jun 2.
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.
NK细胞的抗转移活性在多种癌症类型中已得到充分证实，但其转移浸润及获得抗肿瘤特性的潜在机制仍不清楚。在此，我们研究了在结直肠癌（CRC）肝转移（LM）环境中促进生成ILC1样CD49a+NK细胞群体所需的细胞和分子因素。我们发现，在MC38小鼠模型中，CD49a+NK细胞在转移浸润的NK细胞中具有最高的细胞毒性能力。此外，趋化因子受体CXCR3促进了CD49a+NK细胞在转移灶中的积累和持久性，在转移灶中，NK细胞与巨噬细胞在富含CXCL9和CXCL10的区域共定位。通过挖掘一组未经治疗的CRC患者的已发表scRNA-seq数据集，我们证实了CXCR3+NK细胞在转移样本中的积累。在NKp46+细胞中条件性缺失Cxcr3以及抗体介导的转移相关巨噬细胞耗竭会损害CD49a+NK细胞的发育，表明CXCR3和巨噬细胞有助于NK细胞在LM中的有效定位和极化。相反，CXCR3阴性NK细胞在转移灶中维持CD49a-表型，实质浸润和肿瘤杀伤能力降低。此外，在一个独立的SL4诱导的CRC转移模型中，CD49a+NK细胞的积累受到损害，该模型无法积累CXCL9+巨噬细胞。总之，我们的结果突出了CXCR3/配体轴在促进CRC肝转移中巨噬细胞依赖性NK细胞积累和功能维持方面的作用。
