Pivotal Role for Cxcr2 in Regulating Tumor-Associated Neutrophil in Breast Cancer

Colin Timaxian (1, 2) , Christoph F A Vogel (3) , Charlotte Orcel (1) , Diana Vetter (1) , Camille Durochat (1) , Clarisse Chinal (1) , Phuong Nguyen (1) , Marie-Laure Aknin (4) , Françoise Mercier-Nomé (4) , Davy Martin (1) , Isabelle Raymond-Letron (5, 6) , Thi-Nhu-Ngoc Van (1) , Sarah D Diermeier (7) , Anastasia Godefroy (8) , Magali Gary-Bobo (8) , Franck Molina (1) , Karl Balabanian (2, 9) , Gwendal Lazennec (1, 2)

1 Sys2Diag - Sys2Diag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic
2 CNRS GDR 3697 Micronit - Microenvironnement des niches tumorales
3 UC Davis - University of California [Davis]
4 IPSIT - Ingénierie et Plateformes au Service de l'Innovation Thérapeutique
5 ENVT - Ecole Nationale Vétérinaire de Toulouse
6 STROMALab
7 University of Otago [Dunedin, Nouvelle-Zélande]
8 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
9 EMily (UMR_S_1160 / U1160) - Ecotaxie, microenvironnement et développement lymphocytaire

Chemokines present in the tumor microenvironment are essential for the control of tumor progression. We show here that several ligands of the chemokine receptor Cxcr2 were up-regulated in the PyMT (polyoma middle T oncogene) model of breast cancer. Interestingly, the knock-down of Cxcr2 in PyMT animals led to an increased growth of the primary tumor and lung metastasis. The analysis of tumor content of PyMT-Cxcr2−/− animals highlighted an increased infiltration of tumor associated neutrophils (TANs), mirrored by a decreased recruitment of tumor associated macrophages (TAMs) compared to PyMT animals. Analysis of PyMT-Cxcr2−/− TANs revealed that they lost their killing ability compared to PyMT-Cxcr2+/+ TANs. The transcriptomic analysis of PyMT-Cxcr2−/− TANs showed that they had a more pronounced pro-tumor TAN2 profile compared to PyMT TANs. In particular, PyMT-Cxcr2−/− TANs displayed an up-regulation of the pathways involved in reactive oxygen species (ROS) production and angiogenesis and factors favoring metastasis, but reduced apoptosis. In summary, our data reveal that a lack of Cxcr2 provides TANs with pro-tumor effects.

Mots clés: chemokine receptors; breast cancer; Cxcr2; neutrophils; tumor microenvironment

Domaines: Cancer; Génomique, Transcriptomique et Protéomique [q-bio.GN]

Colin Timaxian, Christoph F A Vogel, Charlotte Orcel, Diana Vetter, Camille Durochat, et al.. Pivotal Role for Cxcr2 in Regulating Tumor-Associated Neutrophil in Breast Cancer. Cancers, 2021, 13 (11), pp.2584. ⟨10.3390/cancers13112584⟩. ⟨hal-03236738⟩