The PD-1 Axis Enforces an Anatomical Segregation of CTL Activity that Creates Tumor Niches after Allogeneic Hematopoietic Stem Cell Transplantation

•Allogeneic HSCT results in extensive differences of donor CTL activity between organs•Differential upregulation of PD-1 ligands in tissues compartmentalizes CTL activity•The anatomical compartmentalization of CTL activity creates niches for tumor escape•Anti-PD-1 treatment homogenizes the efficacy of the graft-versus-tumor effect

SummaryAllogeneic 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.

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