Bone marrow CD8 T cells express high frequency of PD-1 and exhibit reduced anti-leukemia response in newly diagnosed AML patients

Jia, Bei; Wang, Liru; Claxton, David F.; Ehmann, W. Christopher; Rybka, Witold B.; Mineishi, Shin; Rizvi, Syed; Shike, Hiroko; Bayerl, Michael G.; Schell, Todd D.; Hohl, Raymond J.; Zheng, Hong

doi:10.1038/s41408-018-0069-4

Cited by 50 publications

(41 citation statements)

References 16 publications

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“…For therapies that require isolation of T cells expressing inhibitory receptors [37,38], T cell exhaustion and dysfunction pose a major challenge. However, the present study and other recently published works suggested that CD8 + PD-1 + cells had extensive clonal expansion [21], produced IFN-γ and lysed tumors in vitro [18]. This adds to evidence that the process of T cell dysfunction associated with co-expressing inhibitory receptors is reversible, and the enrichment of tumor-reactive cells for patient treatment is reproducible.…”

Section: Discussionsupporting

confidence: 79%

“…As a dominant inhibitory receptor, PD-1 is the pivotal mediator that induces CD8 + T cell exhaustion and contributes to T cell impairment. Several previous reports have suggested the functional involvement of PD-1 in AML progression [2,18,30,31]. Compared to the time of diagnosis, for PD-1-expressing CD8 T cells, a signi cantly increased tendency in the bone marrow of relapsed patients and a decreased trend in the bone marrow of patients who had CR were noted in our study (Fig.…”

Section: Tcr Repertoire Distribution Of Cd8 + T Cells Based On Pd-1 Esupporting

confidence: 71%

“…It has become increasingly clear that programmed death-1 (PD-1) is a key regulator of T cell dysfunction that arises from exposure to antigen stimulation [17]. Recent study has reported functional skewing of CD8 + T cells in newly diagnosed AML patients, which is correlated with an upregulation of PD-1 expression [18]. As expected, the response to chemotherapy is associated with upregulation of costimulatory molecules and attenuation of apoptotic signaling [19].…”

Section: Introductionmentioning

confidence: 76%

“…Several studies reported increased levels of PD-1 as well as multiple co-expressing inhibitor receptors (IRs) on CD8 + T cells of AML patients at diagnosis [18,19]. Longitudinal observation of changes in the IRs expression pattern indicate that PD-1 and Tim3, together with several other coinhibitory receptors, are increased in bone marrow CD8 + T cells in non-responders and reduced in responders post chemotherapy [2,36].…”

Section: Discussionmentioning

confidence: 99%

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Clonal Expansion of Bone Marrow CD8+ T Cells in Acute Myeloid Leukemia Patients at New Diagnosis and Post Chemotherapy

Feng

Fang

Kuang

et al. 2020

Preprint

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Background: CD8+ T cells are crucial adaptive immune effectors and express receptors (T cell receptors, TCRs) that specifically recognize and eradicate tumor cells. The diversity of the TCR repertoire is generated by specialized genetic diversification mechanisms, leading to an extremely variable TCR repertoire capable of recognizing a wide range of antigens. However, the variations in CD8+ TCR diversity and their clinical implications in AML patients remain unknown.Methods: CD8+ T cells in 10 healthy donors and 31 AML patients at diagnosis and after chemotherapy were enriched using the Dynabeads CD8 Positive Isolation Kit. Flow cytometry were used for PD-1 expression level analysis of CD8+ T cells and CD8+PD-1+ and CD8+PD-1- T cell sorting. TCRβ deep sequencing was performed to analysis the CD8+ T cells clonal expansion and TCR repertoire diversity.Results: Diminished TCR repertoire diversity and expansional T cell clones were noted in the bone marrow of AML patients. In relapsed patients, T cells were found to be more clonally expanded post chemotherapy when compared to new diagnosis. Moreover, more significantly expanded TCRβ clonotypes were noted in CD8+ PD-1+ T cells than in CD8+ PD-1- T cells regardless of the time point of examination. Conclusions: Our systematic T-cell repertoire analysis may help better characterize CD8+ T cells pre- and post-chemotherapy in AML, which may provide insights into therapeutic strategies in hematological malignancies.

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Section: Discussionsupporting

confidence: 79%

Section: Tcr Repertoire Distribution Of Cd8 + T Cells Based On Pd-1 Esupporting

confidence: 71%

Section: Introductionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Clonal Expansion of Bone Marrow CD8+ T Cells in Acute Myeloid Leukemia Patients at New Diagnosis and Post Chemotherapy

Feng

Fang

Kuang

et al. 2020

Preprint

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“…Jia found that CD8 + T cells in the bone marrow of AML patients were more terminally differentiated, expressing more factors associated with exhaustion and had reduced function (in killing capacity and cytokine production) compared to those in the peripheral blood [48]. They also found higher levels of PD-1 expression in the CD8 + T cells in the bone marrow.…”

Section: T Cellsmentioning

confidence: 96%

Acute Myeloid Leukaemia in Its Niche: the Bone Marrow Microenvironment in Acute Myeloid Leukaemia

et al. 2020

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# AbstractPurpose of Review Acute myeloid leukaemia (AML) is a heterogeneous malignancy for which treatment options remain suboptimal. It is clear that a greater understanding of the biology of the AML niche will enable new therapeutic strategies to be developed in order to improve treatment outcomes for patients. Recent Findings Recent evidence has highlighted the importance of the bone marrow microenvironment in protecting leukaemia cells, and in particular leukaemic stem cells from chemotherapy-induced cell death. This includes mesenchymal stem cells supporting growth and preventing apoptosis, and altered action and secretion profiles of other niche components including adipocytes, endothelial cells and T cells. Summary Here, we provide a detailed overview of the current understanding of the AML bone marrow microenvironment. Clinical trials of agents that mobilise leukaemic stem cells from the bone marrow are currently ongoing and show early promise. Future challenges will involve combining these novel therapies targeted at the AML niche with conventional chemotherapy treatment.

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Immune‐dysregulation harnessing in myeloid neoplasms

Sharifi,

Xu,

Nasiri

et al. 2024

Cancer Medicine

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Myeloid malignancies arise in bone marrow microenvironments and shape these microenvironments in favor of malignant development. Immune suppression is one of the most important stages in myeloid leukemia progression. Leukemic clone expansion and immune dysregulation occur simultaneously in bone marrow microenvironments. Complex interactions emerge between normal immune system elements and leukemic clones in the bone marrow. In recent years, researchers have identified several of these pathological interactions. For instance, recent works shows that the secretion of inflammatory cytokines such as tumor necrosis factor‐α (TNF‐α), from bone marrow stromal cells contributes to immune dysregulation and the selective proliferation of JAK2V617F+ clones in myeloproliferative neoplasms. Moreover, inflammasome activation and sterile inflammation result in inflamed microenvironments and the development of myelodysplastic syndromes. Additional immune dysregulations, such as exhaustion of T and NK cells, an increase in regulatory T cells, and impairments in antigen presentation are common findings in myeloid malignancies. In this review, we discuss the role of altered bone marrow microenvironments in the induction of immune dysregulations that accompany myeloid malignancies. We also consider both current and novel therapeutic strategies to restore normal immune system function in the context of myeloid malignancies.

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Bone marrow CD8 T cells express high frequency of PD-1 and exhibit reduced anti-leukemia response in newly diagnosed AML patients

Cited by 50 publications

References 16 publications

Clonal Expansion of Bone Marrow CD8+ T Cells in Acute Myeloid Leukemia Patients at New Diagnosis and Post Chemotherapy

Clonal Expansion of Bone Marrow CD8+ T Cells in Acute Myeloid Leukemia Patients at New Diagnosis and Post Chemotherapy

Acute Myeloid Leukaemia in Its Niche: the Bone Marrow Microenvironment in Acute Myeloid Leukaemia

Immune‐dysregulation harnessing in myeloid neoplasms

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