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

Abstract

Tumor relapses remain a serious problem after allogeneic stem cell transplantation (alloSCT), 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 programmed death-1 (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 costimulatory molecules such as CD80 and CD86 were not expressed. Thus, immature leukemic progenitor cells seemed 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-γ production of MiHA-specific T cells cocultured 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 augment 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. Furthermore, they suggest that blocking the PD-1 immune checkpoint offers an appealing immunotherapeutic strategy following alloSCT in patients with recurrent or relapsed disease.

• Authors: Wieger J Norde, Frans Maas, Willemijn Hobo, Alan Korman, Michael Quigley, Michel G D Kester, Konnie Hebeda, J H Frederik Falkenburg, Nicolaas Schaap, Theo M de Witte, Robbert van der Voort, Harry Dolstra
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 15 Pg. 5111-22 (Aug 01 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21659460 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Apoptosis Regulatory Proteins
• B7-1 Antigen
• B7-2 Antigen
• B7-H1 Antigen
• CD274 protein, human
• CD86 protein, human
• Minor Histocompatibility Antigens
• Neoplasm Proteins
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Receptors, Purinergic P2X5
• Tumor Necrosis Factor-alpha
• Interferon-gamma

Topics

• Antigens, CD (physiology)
• Apoptosis Regulatory Proteins (antagonists & inhibitors, physiology)
• B7-1 Antigen (biosynthesis)
• B7-2 Antigen (biosynthesis)
• B7-H1 Antigen
• Coculture Techniques
• Gene Expression Profiling
• Gene Expression Regulation, Leukemic (drug effects)
• Hematopoietic Stem Cell Transplantation
• Humans
• Immunologic Memory
• Inflammation
• Interferon-gamma (pharmacology)
• Leukemia, Myeloid (immunology, pathology, surgery)
• Minor Histocompatibility Antigens (immunology)
• Neoplasm Proteins (antagonists & inhibitors, physiology)
• Neoplastic Stem Cells (immunology, metabolism)
• Programmed Cell Death 1 Receptor
• Receptors, Purinergic P2X5 (immunology)
• Recurrence
• T-Cell Antigen Receptor Specificity
• T-Lymphocyte Subsets (immunology)
• Transplantation, Homologous
• Tumor Escape (immunology, physiology)
• Tumor Necrosis Factor-alpha (pharmacology)