title: The PD-1 Axis Enforces an Anatomical Segregation of CTL Activity that Creates Tumor Niches after Allogeneic Hematopoietic Stem Cell Transplantation.
abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a curative treatment for hematologic malignancies, relies on donor cytotoxic T lymphocyte (CTL)-mediated graft-versus-leukemia (GVL) effect. Major complications of HSCT are graft-versus-host disease (GVHD) that targets specific tissues and tumor relapses. However, the mechanisms dictating the anatomical features of GVHD and GVL remain unclear. Here, we show that after HSCT, CTLs exhibited different killing activity in distinct tissues, being highest in the liver and lowest in lymph nodes. Differences were imposed by the microenvironment, partly through differential PD-1 ligand expression, which was strongly elevated in lymph nodes. Two-photon imaging revealed that PD-1 blockade restored CTL sensitivity to antigen and killing in lymph nodes. Weak CTL activity in lymph nodes promoted local tumor escape but could be reversed by anti-PD-1 treatment. Our results uncover a mechanism generating an anatomical segregation of CTL activity that might dictate sites of GVHD and create niches for tumor escape.
authors.affiliation: Dynamics of Immune Responses Unit, Equipe Labéllisée Ligue Contre le Cancer, Institut Pasteur, 75015 Paris, France; INSERM U668, rue du Dr Roux, 75015 Paris, France; Cellule Pasteur, University Paris Diderot, Sorbonne Paris Cité, 75015 Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Michonneau
authors.affiliation: Dynamics of Immune Responses Unit, Equipe Labéllisée Ligue Contre le Cancer, Institut Pasteur, 75015 Paris, France; INSERM U668, rue du Dr Roux, 75015 Paris, France.
authors.forename: Pervinder
authors.initials: P
authors.lastname: Sagoo
authors.affiliation: Dynamics of Immune Responses Unit, Equipe Labéllisée Ligue Contre le Cancer, Institut Pasteur, 75015 Paris, France; INSERM U668, rue du Dr Roux, 75015 Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Breart
authors.affiliation: Dynamics of Immune Responses Unit, Equipe Labéllisée Ligue Contre le Cancer, Institut Pasteur, 75015 Paris, France; INSERM U668, rue du Dr Roux, 75015 Paris, France.
authors.forename: Zacarias
authors.initials: Z
authors.lastname: Garcia
authors.affiliation: Dynamics of Immune Responses Unit, Equipe Labéllisée Ligue Contre le Cancer, Institut Pasteur, 75015 Paris, France; INSERM U668, rue du Dr Roux, 75015 Paris, France.
authors.forename: Susanna
authors.initials: S
authors.lastname: Celli
authors.affiliation: Dynamics of Immune Responses Unit, Equipe Labéllisée Ligue Contre le Cancer, Institut Pasteur, 75015 Paris, France; INSERM U668, rue du Dr Roux, 75015 Paris, France. Electronic address: philippe.bousso@pasteur.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bousso
mesh_terms: D064591:Allografts; D000818:Animals; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006086:Graft vs Host Disease / Q000276:immunology*; D020350:Graft vs Tumor Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*
chemical_list: C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor