PD-1/PD-L1 interactions contribute to functional T cell impairment in patients that relapse with cancer after allogeneic stem cell transplantation

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A group of researchers at the Laboratory of Hematology, Radboud University Nijmegen Medical Centre have recently published an article in Cancer Research. Tumor relapses remain a serious problem after allogeneic stem cell transplantation (SCT), despite the long-term persistence of minor histocompatibility antigen (MiHA)-specific memory CD8+ T cells specific for the tumor.

We hypothesized that these memory T cells may lose their function over time in transplanted patients. Here we offer functional and mechanistic support for this hypothesis, based on immune inhibition by PD-1 expressed on MiHA-specific CD8+ T cells and the associated role of the PD-1 ligand PD-L1 on myeloid leukemia cells, especially under inflammatory conditions. PD-L1 was highly upregulated on immature human leukemic progenitor cells, whereas co-stimulatory molecules such as CD80 and CD86 were not expressed. Thus, immature leukemic progenitor cells appeared to evade the immune system by inhibiting T-cell function via the PD-1/PD-L1 pathway.

Blocking PD-1-signaling using human antibodies led to elevated proliferation and IFN-? production of MiHA-specific T cells co-cultured with PD-L1-expressing leukemia cells. Moreover, patients with relapsed leukemia after initial MiHA-specific T cell responses displayed high PD-L1 expression on CD34+ leukemia cells and increased PD-1 levels on MiHA-specific CD8+ T cells. Importantly, blocking PD-1/PD-L1 interactions augments proliferation of MiHA-specific CD8+ memory T cells from relapsed patients. Taken together, our findings indicate that the PD-1/PD-L pathway can be hijacked as an immune escape mechanism in hematological malignancies. Further, they suggest that blocking the PD-1 immune checkpoint offers an appealing immunotherapeutic strategy following allogeneic SCT in patients with recurrent or relapsed disease.

Norde WJ, Maas F, Hobo W, Korman A, Quigley M, Kester MG, Hebeda K, Falkenburg JH, Schaap N, de Witte TM, van der Voort R, Dolstra H. SourceLaboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Centre.
 
Photo: (fltr) Willemijn Hobo, Wieger Norde, Frans Maas, Harry Dolstra and Robbert van der Voort.

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