CCR2 Influences T Regulatory Cell Migration to Tumors and Serves as a Biomarker of Cyclophosphamide Sensitivity.
The CCL2 chemokine receptor CCR2 drives cancer by mediating the recruitment of monocytes and myeloid-derived suppressor cells to the tumor microenvironment. In this study, we extend the significance of CCR2 in this setting by identifying a new role for it in mediating recruitment of CD4+T regulatory cells (Treg). Following tumor initiation, an expanded population of CCR2+Tregs required CCR2 expression to traffic between draining lymph nodes (dLN) and the tumor. This Treg subset was enriched in the fraction of tumor antigen-specific cells in the dLN, where they displayed an activated immunosuppressive phenotype. Notably, in mouse models, low-dose cyclophosphamide treatment preferentially depleted CCR2+Treg, enhancing priming of tumor-specific CD8+T cells. In the MMTV-PyMT transgenic mouse model of breast cancer and in oral squamous cell carcinoma patients, tumor development was associated with decreased blood frequency and inversely increased tumor frequency of CCR2+Tregs. Our results define a novel subset of CCR2+Treg involved in tumoral immune escape, and they offer evidence that this Treg subset may be preferentially eradicated by low-dose cyclophosphamide treatment. Cancer Res; 76(22); 6483-94. ©2016 AACR.
Sorbonne Universités, UPMC Université Paris 06 UMR_S1135, Institut Universitaire de Cancérologie (IUC), Inserm U1135, CNRS ERL8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
Pierre-Louis
PL
Loyher
Sorbonne Universités, UPMC Université Paris 06 UMR_S1135, Institut Universitaire de Cancérologie (IUC), Inserm U1135, CNRS ERL8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
Juliette
J
Rochefort
Sorbonne Universités, UPMC Université Paris 06 UMR_S1135, Institut Universitaire de Cancérologie (IUC), Inserm U1135, CNRS ERL8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
Camille
C
Baudesson de Chanville
Sorbonne Universités, UPMC Université Paris 06 UMR_S1135, Institut Universitaire de Cancérologie (IUC), Inserm U1135, CNRS ERL8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
Pauline
P
Hamon
Sorbonne Universités, UPMC Université Paris 06 UMR_S1135, Institut Universitaire de Cancérologie (IUC), Inserm U1135, CNRS ERL8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
Géraldine
G
Lescaille
Sorbonne Universités, UPMC Université Paris 06 UMR_S1135, Institut Universitaire de Cancérologie (IUC), Inserm U1135, CNRS ERL8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.|Department of Maxillofacial Surgery, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
Chloé
C
Bertolus
Sorbonne Universités, UPMC Université Paris 06 UMR_S1135, Institut Universitaire de Cancérologie (IUC), Inserm U1135, CNRS ERL8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
Maude
M
Guillot-Delost
Department of Pathology, University of California San Francisco, San Francisco, California.
Matthew F
MF
Krummel
Sorbonne Universités, UPMC Université Paris 06 UMR_S1135, Institut Universitaire de Cancérologie (IUC), Inserm U1135, CNRS ERL8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
François M
FM
Lemoine
Sorbonne Universités, UPMC Université Paris 06 UMR_S1135, Institut Universitaire de Cancérologie (IUC), Inserm U1135, CNRS ERL8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
Christophe
C
Combadière
Sorbonne Universités, UPMC Université Paris 06 UMR_S1135, Institut Universitaire de Cancérologie (IUC), Inserm U1135, CNRS ERL8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France. alexandre.boissonnas@upmc.fr.
Alexandre
A
Boissonnas
D000818:Animals; D015415:Biomarkers; D002465:Cell Movement; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D054390:Receptors, CCR2 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015415:Biomarkers; D054390:Receptors, CCR2; D003520:Cyclophosphamide