The role of leukemia-derived B7-H1 (PD-L1) in tumor–T-cell interactions in humans

Salih, Helmut R.; Wintterle, Sabine; Krusch, Matthias; Kroner, Antje; Huang, Yu; Chen, Lieping; Wiendl, Heinz

doi:10.1016/j.exphem.2006.03.006

Cited by 46 publications

(40 citation statements)

References 24 publications

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“…48 In accordance with our experiments in murine CML models, PD-L1 expression was documented previously on CML and AML patient samples. 49,50 We consequently extended our findings to CML patients. In CML patients, a majority of total CD8 ϩ T cells expressed PD-1, suggesting that the PD-1/PD-L1 interaction may be involved in the induction of CTL inhibition in humans.…”

Section: Discussionmentioning

confidence: 99%

Programmed death 1 signaling on chronic myeloid leukemia–specific T cells results in T-cell exhaustion and disease progression

Mumprecht

Schürch

Schwaller

et al. 2009

Blood

242

181

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Chronic myeloid leukemia (CML) is a malignant myeloproliferative disease with a characteristic chronic phase (cp) of several years before progression to blast crisis (bc). The immune system may contribute to disease control in CML. We analyzed leukemia-specific immune responses in cpCML and bcCML in a retroviral-induced murine CML model. In the presence of cpCML and bcCML expressing the glycoprotein of lymphocytic choriomeningitis virus as a model leukemia antigen, leukemia-specific cytotoxic T lymphocytes (CTLs) became exhausted. They maintained only limited cytotoxic activity, and did not produce interferon-␥ or tumor necrosis factor-␣ or expand after restimulation. CML-specific CTLs were characterized by high expression of programmed death 1 (PD-1), whereas CML cells expressed PD-ligand 1 (PD-L1). Blocking the PD-1/PD-L1 interaction by generating bcCML in PD-1-deficient mice or by repetitive administration of ␣PD-L1 antibody prolonged survival. In addition, we found that PD-1 is up-regulated on CD8 ؉ T cells from CML patients. Taken IntroductionChronic myeloid leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of a hematopoietic stem cell. 1 The disease is bi-or triphasic, comprising a chronic, an accelerated, and a terminal blast phase in which the patients develop an acute leukemia of either myeloid (AML) or, less often, lymphoid (ALL) cell type. More than 90% of all CML cases are associated with the presence of the Philadelphia chromosome, which results from a reciprocal translocation between chromosomes 9 and 22 forming the breakpoint cluster region/ Abelson protein tyrosine kinase (BCR/ABL) fusion protein, a constitutively activated tyrosine kinase. 2,3 Depending on the precise breakpoints in the BCR gene, different forms of BCR/ABL fusion protein with different molecular weights can be generated (p190BCR/ABL, p210BCR/ABL, and p230BCR/ABL). CML patients predominantly express p210BCR/ABL. 1 Currently, BCR/ABL-selective tyrosine kinase inhibitors are the standard treatment for CML. However, resistant clones often develop during treatment. At present, the only curative treatment for CML is allogeneic hematopoietic stem cell transplantation. 4 Several earlier studies suggested that the immune system plays an important role in the control of CML. CML cells are susceptible to lysis by CD8 ϩ T cells 5 and natural killer (NK) cells in vitro. 6 For unknown reasons, CML is the most graft-versus-leukemiasensitive leukemia. 7 In addition, cytotoxic T lymphocytes (CTLs) directed against leukemia antigens are found in CML patients without hematopoietic stem cell transplantation, including CTLs specific for BCR/ABL, overexpressed self-proteins such as proteinase-3, and Wilms tumor 1 protein. 5,8 However, the physiologic relevance of these leukemia-specific CTL responses in the control of CML is unknown. The presence of CTL escape mechanisms during CML disease progression to blast crisis suggests that CTLs are involved in the control of the chronic phase of the disease. ...

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Section: Discussionmentioning

confidence: 99%

Programmed death 1 signaling on chronic myeloid leukemia–specific T cells results in T-cell exhaustion and disease progression

Mumprecht

Schürch

Schwaller

et al. 2009

Blood

242

181

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“…This and our data are in contrast with an earlier study that assessed PD-L1 expression in 30 heterogenous acute leukemia patients and found that 57% of patients expressed PD-L1 at diagnosis on leukemic cells. 43 The serial measurement of PD-L1 expression on ATLL cells clearly needs to be carried out to determine the significance of PD-L1 expression for the disease characteristics.…”

Section: Discussionmentioning

confidence: 99%

PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients

et al. 2008

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Adult T-cell leukemia/lymphoma (ATLL) develops after infection with human T-cell leukemia virus-1 (HTLV-1) after a long latency period. The negative regulatory programmed death-1/ programmed death-1 ligand 1 (PD-1/PD-L1) pathway has been implicated in the induction of cytotoxic T-lymphocyte (CTL) exhaustion during chronic viral infection along with tumor escape from host immunity. To determine whether the PD-1/ PD-L1 pathway could be involved in the establishment of persistent HTLV-1 infections and immune evasion of ATLL cells in patients, we examined PD-1/PD-L1 expression on cells from 27 asymptomatic HTLV-1 carriers (ACs) and 27 ATLL patients in comparison with cells from 18 healthy donors. PD-1 expression on HTLV-1-specific CTLs from ACs and ATLL patients was dramatically elevated. In addition, PD-1 expression was significantly higher on CD8 þ T cells along with cytomegalovirus (CMV)-and Epstein-Barr virus (EBV)-specific CTLs in ATLL patients compared with ACs and control individuals. Primary ATLL cells in 21.7% of ATLL patients expressed PD-L1, whereas elevated expression was not observed in cells from ACs. Finally, in functional studies, we observed that an anti-PD-L1 antagonistic antibody upregulated HTLV-1-specific CD8 þ T-cell response. These observations suggest that the PD-1/ PD-L1 pathway plays a role in fostering persistent HTLV-1 infections, which may further ATLL development and facilitate immune evasion by ATLL cells.

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“…There are two known ligands for PD-1: B7-H1/PD-L1, the predominant mediator of PD-1-dependent immunosuppression, and B7-DC/PD-L2. PD-L1 is expressed on human tumor cells, including leukemia, NHL, and Hodgkin's lymphoma [14][15][16][17][18] and may participate in tumor evasion [19].…”

Section: Anti-pd-1 Mabmentioning

confidence: 99%

Immunomodulating antibodies and drugs for the treatment of hematological malignancies

Houot

Kohrt

Goldstein

et al. 2011

Cancer Metastasis Rev

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The aim of cancer immunotherapy is to induce immune cells to kill tumor and promote immunological memory that protects against tumor recurrence. Most current immunotherapies, such as monoclonal antibodies (mAb), target the tumor cells directly. Advances in our understanding of the immune system such as the role of co-stimulatory and co-inhibitory receptors, and the advent of new immunomodulatory agents provide new opportunities to target the immune system and enhance anti-tumor immune responses. These promising agents include immunomodulating mAbs, Toll-like receptor agonists, IMiDs, and cytokines. In this review, we discuss the current results of immunomodulating agents in the treatment of hematological malignancies and propose applications that include targeting of the innate and adaptive immune systems as well as combinations with tumor-specific mAbs.

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The role of leukemia-derived B7-H1 (PD-L1) in tumor–T-cell interactions in humans

Cited by 46 publications

References 24 publications

Programmed death 1 signaling on chronic myeloid leukemia–specific T cells results in T-cell exhaustion and disease progression

Programmed death 1 signaling on chronic myeloid leukemia–specific T cells results in T-cell exhaustion and disease progression

PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients

Immunomodulating antibodies and drugs for the treatment of hematological malignancies

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