title: CXCL12 mediates immunosuppression in the lymphoma microenvironment after allogeneic transplantation of hematopoietic cells.
abstract: 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.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Freiburg University Medical Center, Albert Ludwigs University, Hugstetterstr. 55, 79106 Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Dürr
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.forename: Annette
authors.initials: A
authors.lastname: Schmitt-Graeff
authors.forename: Ulrike V
authors.initials: UV
authors.lastname: Gerlach
authors.forename: Ralph
authors.initials: R
authors.lastname: Graeser
authors.forename: Sophie
authors.initials: S
authors.lastname: Krüger
authors.forename: Armin
authors.initials: A
authors.lastname: Gerbitz
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
authors.forename: Jürgen
authors.initials: J
authors.lastname: Finke
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000276:immunology*; D018925:Chemokines / Q000096:biosynthesis; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016219:Immunotherapy, Adoptive; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054367:Receptors, CXCR3 / Q000276:immunology; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D054377:Chemokine CXCL12; D018925:Chemokines; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4