Microenvironment and Immunology PD-1/PD-L1 Interactions Contribute to Functional T-Cell Impairment in Patients Who Relapse with Cancer After Allogeneic Stem Cell Transplantation

Tumor relapses remain a serious problem after allogeneic stem cell transplantation (alloSCT), despite the long-term persistence of minor histocompatibility antigen (MiHA)-specific memory CD8þ 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 CD8þ 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-g 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 CD34þ leukemia cells and increased PD-1 levels on MiHA-specific CD8þ T cells. Importantly, blocking PD-1/PD-L1 interactions augment proliferation of MiHA-specific CD8þ 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. Cancer Res; 71(15); 5111–22. 2011 AACR. Introduction Alloreactive CD8þ T cells play a crucial role in the graftversus-tumor (GVT) response following allogeneic stem cell transplantation (alloSCT) and donor lymphocyte infusion (DLI; ref. 1). In HLA-matched alloSCT, these alloreactive CD8þ T-cell responses are directed against minor histocompatibility antigens (MiHA; ref. 2). Previously, we have characterized CD8þ T-cell immunity toward a hematopoieticrestricted MiHA, designated LRH-1, which is presented by HLA-B7 and encoded by the P2 5 purinergic receptor gene (3). LRH-1–specific CD8þ T-cell responses can be frequently detected in myeloid leukemia patients following DLI, and has been associated with leukemic remission (3, 4). Moreover, we showed that CD34þ myeloid leukemia progenitor cells can be efficiently targeted in vitro by LRH-1–specific CD8þ CTLs, indicating that these CTLs play a significant role in graftversus-leukemia (GVL)-specific immunity. However, we have observed that despite the presence of LRH-1–specific CD8þ memory T (Tmem) cells for many years, late relapses do occur in patients with advanced myeloid leukemia. Furthermore, we noted that LRH-1–specific CD8þ Tmem cells do not always efficiently expand with recurrence of leukemia cells, suggesting that these T cells become functionally impaired. Mechanisms exploited by tumor cells to inhibit CD8þ Tcell–mediated immunity include disruption of antigen presentation, downregulation of HLAmolecules, and induction of immunosuppressive components such as programmed death1 (PD-1) signaling (5, 6). PD-1 plays a crucial role in T-cell regulation in various immune responses and is involved in peripheral tolerance, autoimmunity, infection, and antitumor immunity (7). Elevated PD-1 expression on antigen-specific Authors' Affiliations: Departments of Laboratory Medicine—Laboratory of Hematology, Hematology, Tumor Immunology, and Pathology, Radboud University Nijmegen Medical Centre, Nijmegen; Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands; Department of Biologics Discovery California, Bristol-Meyers Squibb, Milpitas, California; Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Corresponding Author: Harry Dolstra, Department of Laboratory Medicine—Laboratory of Hematology, Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: 31-24-3619753; Fax: 31-24-3568408; E-mail: [email protected] doi: 10.1158/0008-5472.CAN-11-0108 2011 American Association for Cancer Research. Cancer Research www.aacrjournals.org 5111 on July 29, 2017. © 2011 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Published OnlineFirst June 9, 2011; DOI: 10.1158/0008-5472.CAN-11-0108