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

Abstract

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. ...

Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy

“…Similar overexpression of PD-1 was observed in CD8 ϩ cells from patients with CML. 42 However, because CML is particularly responsive to immunomodulatory therapies, such as interferon ␣ and donor lymphocyte infusions, it is probable that immunologic defense mechanisms have not been permanently compromised.…”

Do we have to kill the last CML cell?

“…The importance of functional impairment of the anti-leukaemic CTL response was further demonstrated in a mouse model of CML in which upregulation of the programmed cell death-1 receptor was associated with immune exhaustion and disease progression. 66 Manipulation of the co-stimulatory molecules that contribute to immune exhaustion might in the future open up a novel class of therapeutics for CML.…”

Mechanism of T cell exhaustion in a chronic environment

“…Tumor antigen-specific T cells with high tumor antigen load have been shown to respond similar to virus-specific T cells upon chronic infection. Furthermore, CD8 + tumor infiltrating lymphocytes (TILs) show low levels of CD25 and CD127 expression and thus are refractory to IL-2 and IL-7 signaling, indicating that they are unable to proliferate, produce effector cytokines, and differentiate into functional memory cells (21). For example, CML-specific CD8 T cells exhibit decreased production of effector cytokines such as IFN-γ, TNF-α, and IL-2 in a retroviral-induced murine CML model (21).…”

“…Furthermore, CD8 + tumor infiltrating lymphocytes (TILs) show low levels of CD25 and CD127 expression and thus are refractory to IL-2 and IL-7 signaling, indicating that they are unable to proliferate, produce effector cytokines, and differentiate into functional memory cells (21). For example, CML-specific CD8 T cells exhibit decreased production of effector cytokines such as IFN-γ, TNF-α, and IL-2 in a retroviral-induced murine CML model (21). Cancer-germline antigen NY-ESO-1-specific CD8 T cells represent a highly dysfunctional population of tumor-induced T cells in patients with advanced melanoma (22).…”

“…A strong correlation between PD-1 ligand expression on tumor cells and unfavorable prognosis has been demonstrated for various cancers (38)(39)(40)(41)(42)(43)(44). Importantly, high expression of PD-1 on TILs has been reported (21,23,45), and PD-1 blockade has been shown to enhance the frequency of cytokine-producing cells (45). Currently, two humanized monoclonal antibodies against PD-1, ONO-4538/MDX-1106 and CT011, are in clinical trials for treatment of cancer and HCV infection.…”