Chronic myelogenous leukemia maintains specific CD8⁺ T cells through IL‐7 signaling

Abstract

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease of hematopoietic stem cells. The disease progresses after several years from an initial chronic phase to a blast phase. Leukemia-specific T cells are regularly detected in CML patients and may be involved in the immunological control of the disease. Here, we analyzed the role of leukemia-specific CD81 T cells in CML disease control and the mechanism that maintains CD8 1 T-cell immunosurveillance in a retroviral-induced murine CML model. To study antigen-specific immune responses, the glycoprotein of the lymphocytic choriomeningitis virus was used as model leukemia antigen. Leukemiaspecific CTL activity was detectable in vivo in CML mice and depletion of CD8 1 T cells rapidly led to disease progression. CML-specific CTL were characterized by the expression of the IL-7 receptor a-chain. In addition, leukemia cells produced IL-7 that was crucial for the maintenance of leukemia-specific CTL and for disease control. Therefore, CML cells maintain the specific CD8 1 T-cell-mediated immune control by IL-7 secretion. This results in prolonged control of disease and probably contributes to the characteristic chronic phase of the disease.Key words: CD8 1 T cells . Chronic myelogenous leukemia . IL-7 signaling Supporting Information available online IntroductionChronic myelogenous leukemia (CML) is a malignant clonal disease originating from a pluripotent hematopoietic stem cell expressing the reciprocal translocation t(9;22), which forms the oncogenic BCR/ABL fusion protein. BCR/ABL is a constitutively activated tyrosine kinase which plays a critical role in the pathogenesis of CML. After several years and acquisition of a second genetic abnormality, the disease progresses from the chronic phase to terminal blast phase in which the patients develop an acute leukemia of either myeloid (AML) or, less frequent, lymphoid (ALL) cell type [1][2][3]. For unknown reasons, CML seems to be the most immunogenic leukemia. Experiences from stem cell transplantations (SCT) suggest that T cells play an important role in the immunological control of CML. After allogeneic SCT, recipients of T-cell-depleted grafts have a higher incidence of relapses, and post-transplant relapses can be restored to permanent molecular remissions by donor lymphocyte infusions [4,5]. In addition, specific CTL recognizing leukemia antigens such as BCR/ABL, proteinase-3 and Wilms tumor 1 protein have been identified in CML patients without SCT [6]. However, in the peripheral blood à These authors have contributed equally to this work. 2720of CML patients, only low-avidity CTL were detectable. Highavidity CTL might have been deleted through apoptotic processes due to the persistence of the CML [7]. Nevertheless, CML-specific CTL may be involved in the control of the leukemia in the chronic phase over several years and coexist with the leukemia. The mechanisms controlling this delicate balance between the immune system and leukemia are largely unknown. CD8 1 T cells are activated and dev...

Cytotoxic T cells induce proliferation of chronic myeloid leukemia stem cells by secreting interferon-γ

“…with depleting anti-CD8 monoclonal antibody (mAb), starting 12 d after transplantation. This treatment depletes CD8 + T cells from peripheral blood to below detection limits of FACS (not depicted) and leads to rapid CML progression (Mumprecht et al, 2010). Control H8 CML mice were left untreated.…”

Regulation of hematopoietic and leukemic stem cells by the immune system

“… 18 , 138 In an experimental model of CML, depletion of CD8 + T cells by mAbs led to rapid disease progression, documenting an important role of CTLs in the immunosurveillance of leukemia. 139 The role of CD4 + T cells in leukemia is less clear and CD4 + T cells have been shown to be dysfunctional in vivo . 140 Therefore, there is ample evidence that antigen-specific immune responses toward the leukemia are elicited.…”

Leukemia’s Next Top Model? Syngeneic Models to Advance Adoptive Cellular Therapy

“…Mumprecht et al determined that mice that received a lower tumor burden and had disease elimination developed a LCMV-gp33-specific CTL response, while mice that had CML progression lacked persistence of CTLs (40). In a follow up study, they determined that elimination of CD8+ T cells in a CML model led to disease progression and that IL-7 secreted by CML helped maintain a CTL response, leading to stable disease as it is characteristic of chronic phase CML (41). This data highlights the importance of syngeneic modeling cellular immunotherapies to pursue effective non-cellular therapy-based combinations.…”