CXCL12 Mediates Immunosuppression in the Lymphoma Microenvironment after Allogeneic Transplantation of Hematopoietic Cells

被引:51
作者
Duerr, Christoph [1 ,2 ]
Pfeifer, Dietmar [1 ]
Claus, Rainer [3 ]
Schmitt-Graeff, Annette [4 ]
Gerlach, Ulrike V. [4 ]
Graeser, Ralph [5 ]
Krueger, Sophie [1 ]
Gerbitz, Armin [6 ]
Negrin, Robert S. [7 ]
Finke, Juergen [1 ]
Zeiser, Robert [1 ]
机构
[1] Univ Freiburg, Freiburg Univ Med Ctr, Div Hematol & Oncol, Dept Med, D-79106 Freiburg, Germany
[2] Univ Freiburg, Dept Biol, D-79106 Freiburg, Germany
[3] German Canc Res Ctr, Dept Epigenom & Canc Risk Factors, Heidelberg, Germany
[4] Univ Freiburg, Freiburg Univ Med Ctr, Dept Pathol, D-79106 Freiburg, Germany
[5] Tumor Biol Ctr, Freiburg, Germany
[6] Univ Klinikum Erlangen, Med Klin 5, Erlangen, Germany
[7] Stanford Univ Sch Med, Dept Med, Div Blood & Marrow Transplantat, Stanford, CA USA
关键词
REGULATORY T-CELLS; VERSUS-HOST-DISEASE; DENDRITIC CELLS; BONE-MARROW; HODGKIN-LYMPHOMA; INHIBITION; CANCER; TUMORS; SUPPRESSION; TRAFFICKING;
D O I
10.1158/0008-5472.CAN-10-1943
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Clinical studies indicate a role of allogeneic hematopoietic cell transplantation (alloHCT) for patients with refractory or recurrent B-cell lymphoma (BCL) indicative of a graft-versus-tumor effect. However, the relevance of local immunosuppression in the BCL microenvironment by donor-derived regulatory T cells (Treg) after alloHCT is unclear. Therefore, we studied Treg recruitment after alloHCT in different murine BCL models and the impact of lymphoma-derived chemoattractive signals. Luciferase transgenic Tregs accumulated in murine BCL microenvironment and microarray-based analysis of BCL tissues revealed increased expression of CXCL9, CXCL10, and CXCL12. In vivo blocking identified the CXCR4/CXCL12 axis as being critical for Treg attraction toward BCL. In contrast to Tregs, effector T cells displayed low levels of CXCR4 and were not affected by the pharmacologic blockade. Most important, blocking CXCR4 not only reduced Treg migration toward tumor tissue but also enhanced antitumor responses after alloHCT. CXCL12 production was dependent on antigen-presenting cells (APC) located in the lymphoma microenvironment, and their diphtheria-toxin receptor (DTR)-based depletion in CD11c. DTR-Tg mice significantly reduced Treg accumulation within BCL tissue. CXCL12 was also detected in human diffuse, large BCL tissues indicative of its potential clinical relevance. In conclusion, we demonstrate that Tregs are recruited toward BCL after alloHCT by infiltrating host APCs in a CXCL12-dependent fashion. Blocking CXCR4 enhanced antitumor effects and prolonged survival of tumor-bearing mice by reducing local Treg accumulation, indicating that CXCR4 is a potential target to interfere with tumor escape after alloHCT. Cancer Res; 70(24); 10170-81. (C) 2010 AACR.
引用
收藏
页码:10170 / 10181
页数:12
相关论文
共 49 条
[1]   Xeroderma pigmentosum skin: an immune privilege site for tumor development [J].
Abid, Kalthoum ;
El Mezni, Faouzi ;
Kamoun, Mohamed Ridha ;
Fazaa, Becima ;
Zermani, Rachida ;
Hadouchi, Chokri ;
Hamzaoui, Kamel .
JOURNAL OF CUTANEOUS PATHOLOGY, 2010, 37 (04) :452-459
[2]   Follicular lymphoma B cells induce the conversion of conventional CD4+ T cells to T-regulatory cells [J].
Ai, Weiyun Z. ;
Hou, Ling-Zhou ;
Zeiser, Robert ;
Czerwinski, Debra ;
Negrin, Robert S. ;
Levy, Ronald .
INTERNATIONAL JOURNAL OF CANCER, 2009, 124 (01) :239-244
[3]   CD4+CD25+FOXP3+ T regulatory cells reconstitute and accumulate in the bone marrow of patients with multiple myeloma following allogeneic stem cell transplantation [J].
Atanackovic, Djordje ;
Cao, Yanran ;
Luetkens, Tim ;
Panse, Jens ;
Faltz, Christiane ;
Arfsten, Julia ;
Bartels, Katrin ;
Wolschke, Christine ;
Eiermann, Thomas ;
Zander, Axel R. ;
Fehse, Boris ;
Bokemeyer, Carsten ;
Kroger, Nicolaus .
HAEMATOLOGICA, 2008, 93 (03) :423-430
[4]   A new liposomal formulation of Gemcitabine is active in an orthotopic mouse model of pancreatic cancer accessible to bioluminescence imaging [J].
Bornmann, C. ;
Graeser, R. ;
Esser, N. ;
Ziroli, V. ;
Jantscheff, P. ;
Keck, T. ;
Unger, C. ;
Hopt, U. T. ;
Adam, U. ;
Schaechtele, C. ;
Massing, U. ;
Von Dobschuetz, E. .
CANCER CHEMOTHERAPY AND PHARMACOLOGY, 2008, 61 (03) :395-405
[5]   Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1 [J].
Ceradini, DJ ;
Kulkarni, AR ;
Callaghan, MJ ;
Tepper, OM ;
Bastidas, N ;
Kleinman, ME ;
Capla, JM ;
Galiano, RD ;
Levine, JP ;
Gurtner, GC .
NATURE MEDICINE, 2004, 10 (08) :858-864
[6]   Regulatory T cells prevent CD8 T cell maturation by inhibiting CD4 th cells at tumor sites [J].
Chaput, Nathalie ;
Darrasse-Jeze, Guillaume ;
Bergot, Anne-Sophie ;
Cordier, Corinne ;
Ngo-Abdalla, Stacie ;
Klatzmann, David ;
Azogui, Orly .
JOURNAL OF IMMUNOLOGY, 2007, 179 (08) :4969-4978
[7]   Requirement of CD80+ costimulation for rejection of ocular tumors and termination of immune privilege [J].
Chen, Peter W. ;
Uno, Tohishiko ;
Ksander, Bruce R. .
EXPERIMENTAL EYE RESEARCH, 2006, 83 (03) :574-583
[8]   Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival [J].
Curiel, TJ ;
Coukos, G ;
Zou, LH ;
Alvarez, X ;
Cheng, P ;
Mottram, P ;
Evdemon-Hogan, M ;
Conejo-Garcia, JR ;
Zhang, L ;
Burow, M ;
Zhu, Y ;
Wei, S ;
Kryczek, I ;
Daniel, B ;
Gordon, A ;
Myers, L ;
Lackner, A ;
Disis, ML ;
Knutson, KL ;
Chen, LP ;
Zou, WP .
NATURE MEDICINE, 2004, 10 (09) :942-949
[9]   HIGHLY POTENT AND SELECTIVE-INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS BY THE BICYCLAM DERIVATIVE JM3100 [J].
DE CLERCQ, E ;
YAMAMOTO, N ;
PAUWELS, R ;
BALZARINI, J ;
WITVROUW, M ;
DEVREESE, K ;
DEBYSER, Z ;
ROSENWIRTH, B ;
PEICHL, P ;
DATEMA, R ;
THORNTON, D ;
SKERLJ, R ;
GAUL, F ;
PADMANABHAN, S ;
BRIDGER, G ;
HENSON, G ;
ABRAMS, M .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1994, 38 (04) :668-674
[10]   Phase III Prospective Randomized Double-Blind Placebo-Controlled Trial of Plerixafor Plus Granulocyte Colony-Stimulating Factor Compared With Placebo Plus Granulocyte Colony-Stimulating Factor for Autologous Stem-Cell Mobilization and Transplantation for Patients With Non-Hodgkin's Lymphoma [J].
DiPersio, John F. ;
Micallef, Ivana N. ;
Stiff, Patrick J. ;
Bolwell, Brian J. ;
Maziarz, Richard T. ;
Jacobsen, Eric ;
Nademanee, Auayporn ;
McCarty, John ;
Bridger, Gary ;
Calandra, Gary .
JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (28) :4767-4773