Graft-versus-host disease reduces regulatory T-cell migration into the tumour tissue.
The therapeutic principle of allogeneic haematopoietic cell transplantation (allo-HCT) is based on an active donor immune system that eliminates host-derived tumour cells. We hypothesized that in addition to the alloantigen-driven anti-tumour response, disruption of the immunological microenvironment within the tumour is responsible for its elimination after allo-HCT. We observed that induction of graft-versus-host disease (GvHD) significantly reduced the abundance of luc(+)  FoxP3(+)  regulatory T (Treg) cells in the tumour tissue, which is indicative of impaired or over-ridden tumour recruitment signals towards Treg cells. Analysis of the intestines and liver revealed chemokines and purine nucleotides as candidates for attracting Treg to these sites of inflammation. Despite its expression on tissue-residing Treg cells, the chemokine receptor CCR3 was not critical for Treg-cell function following allo-HCT. Extracellular ATP can attract immune cells via P2Y2. P2Y2 was found to be expressed on Treg cells, and we found a partial reduction of GvHD prevention when P2Y2(-/-)  rather than P2Y2(+/+)  Treg cells were given. Exogenous local inflammation reduced Treg-cell accumulation in the tumour, suggesting a potential clinical approach to prevent Treg-cell-mediated tumour escape. In conclusion, we demonstrate that GvHD-related inflammation reduced Treg-cell numbers at the tumour sites, which may in turn help to explain the observation that patients with GvHD have a lower risk of tumour relapse.
Department of Haematology and Oncology, Freiburg University Medical Centre, Albert-Ludwigs-University, Freiburg, Germany.
Christoph
C
Dürr
Marie
M
Follo
Marco
M
Idzko
Wilfried
W
Reichardt
Robert
R
Zeiser
D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D006086:Graft vs Host Disease / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D007249:Inflammation; D007422:Intestines / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009281:Naphthalenes / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D054397:Receptors, CCR3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D058473:Receptors, Purinergic P2Y2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D014184:Transplantation, Homologous; D059016:Tumor Microenvironment / Q000276:immunology
C515351:Ccr3 protein, mouse; D009281:Naphthalenes; D054397:Receptors, CCR3; D058473:Receptors, Purinergic P2Y2; C417503:SB 328437; D010649:Phenylalanine