Netrin-1 blockade inhibits tumor associated Myeloid-derived suppressor cells, cancer stemness and alleviates resistance to chemotherapy and immune checkpoint inhibitor

Drug resistance and cancer relapse represent significant therapeutic challenges after chemotherapy or immunotherapy, and a major limiting factor for long-term cancer survival. Netrin-1 was initially identified as a neuronal navigation cue but has more recently emerged as an interesting target for ca...

Full description

Saved in:
Bibliographic Details
Published in:Cell death and differentiation 2023-10, Vol.30 (10), p.2201-2212
Main Authors: Ducarouge, Benjamin, Redavid, Anna-Rita, Victoor, Camille, Chira, Ruxanda, Fonseca, Aurélien, Hervieu, Maëva, Bergé, Roméo, Lengrand, Justine, Vieugué, Pauline, Neves, David, Goddard, Isabelle, Richaud, Mathieu, Laval, Pierre-Alexandre, Rama, Nicolas, Goldschneider, David, Paradisi, Andrea, Gourdin, Nicolas, Chabaud, Sylvie, Treilleux, Isabelle, Gadot, Nicolas, Ray-Coquard, Isabelle, Depil, Stéphane, Decaudin, Didier, Némati, Fariba, Marangoni, Elisabetta, Mery-Lamarche, Eliane, Génestie, Catherine, Tabone-Eglinger, Séverine, Devouassoux-Shisheboran, Mojgan, Moore, Kathryn J, Gibert, Benjamin, Mehlen, Patrick, Bernet, Agnes
Format: Article
Language:English
Subjects:
Animal models
Animals
Blocking antibodies
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer
Cancer therapies
Cell Line, Tumor
Chemotherapy
Drug resistance
Drug Resistance, Neoplasm - drug effects
Female
Humans
Immune checkpoint inhibitors
Immune Checkpoint Inhibitors - pharmacology
Immune Checkpoint Inhibitors - therapeutic use
Immunosuppressive agents
Immunotherapy
Life Sciences
Mice
Myeloid-Derived Suppressor Cells - drug effects
Myeloid-Derived Suppressor Cells - metabolism
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Netrin-1
Netrin-1 - metabolism
Ovarian cancer
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - pathology
Stem cells
Suppressor cells
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Drug resistance and cancer relapse represent significant therapeutic challenges after chemotherapy or immunotherapy, and a major limiting factor for long-term cancer survival. Netrin-1 was initially identified as a neuronal navigation cue but has more recently emerged as an interesting target for cancer therapy, which is currently clinically investigated. We show here that netrin-1 is an independent prognostic marker for clinical progression of breast and ovary cancers. Cancer stem cells (CSCs)/Tumor initiating cells (TICs) are hypothesized to be involved in clinical progression, tumor relapse and resistance. We found a significant correlation between netrin-1 expression and cancer stem cell (CSC) markers levels. We also show in different mice models of resistance to chemotherapies that netrin-1 interference using a therapeutic netrin-1 blocking antibody alleviates resistance to chemotherapy and triggers an efficient delay in tumor relapse and this effect is associated with CSCs loss. We also demonstrate that netrin-1 interference limits tumor resistance to immune checkpoint inhibitor and provide evidence linking this enhanced anti-tumor efficacy to a decreased recruitment of a subtype of myeloid-derived suppressor cells (MDSCs) called polymorphonuclear (PMN)-MDSCs. We have functionally demonstrated that these immune cells promote CSCs features and, consequently, resistance to anti-cancer treatments. Together, these data support the view of both a direct and indirect contribution of netrin-1 to cancer stemness and we propose that this may lead to therapeutic opportunities by combining conventional chemotherapies and immunotherapies with netrin-1 interfering drugs.
ISSN:1350-9047
1476-5403
1476-5403
DOI:10.1038/s41418-023-01209-x