Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia

Lamble, Adam J.; Kosaka, Yoko; Laderas, Ted; Maffit, Allie; Kaempf, Andy; Brady, Lauren; Wang, Weiwei; Long, Nicola; Saultz, Jennifer N.; Mori, Motomi; Soong, David; LeFave, Clare V.; Huang, Fei; Adams, Homer; Loriaux, Marc; Tognon, Cristina E.; Lo, Pierrette; Tyner, Jeffrey W.; Fan, Guang; McWeeney, Shannon K.; Druker, Brian J.; Lind, Evan F.

doi:10.1073/pnas.1916206117

Cited by 64 publications

(55 citation statements)

References 79 publications

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“…It is possible that the molecular crosstalk between malignant cells and the bone marrow niche gradually remodels normal niche behavior to foster leukemic growth and attenuate normal hematopoiesis. Also poorly understood is whether leukemias affect the long-term maintenance of adaptive immune cells that require access to critical bone marrow survival niches, though recent studies suggest that may be the case (173,174).…”

Section: Leukemia and Its Impact On Bone Marrow Niches Hematopoiesismentioning

confidence: 99%

Hematopoietic Stem Cell Niches and Signals Controlling Immune Cell Development and Maintenance of Immunological Memory

et al. 2020

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Studies over the last couple of decades have shown that hematopoietic stem cells (HSCs) are critically dependent on cytokines such as Stem Cell Factor and other signals provided by bone marrow niches comprising of mesenchymal stem and progenitor cells (MSPCs) and endothelial cells (ECs). Because of their critical roles in HSC maintenance the niches formed by MSPCs and ECs are commonly referred to as HSC niches. For the most part, the signals required for HSC maintenance act in a short-range manner, which imposes the necessity for directional and positional cues in order for HSCs to localize and be retained properly in stem cell niches. The chemokine CXCL12 and its Gαi protein coupled receptor CXCR4, besides promoting HSC quiescence directly, also play instrumental roles in enabling HSCs to access bone marrow stem cell niches. Recent studies have revealed, however, that HSC niches also provide a constellation of hematopoietic cytokines that are critical for the production of most, if not all, blood cell types. Some hematopoietic cytokines, namely IL-7 and IL-15 produced by HSC niches, are not only required for lymphopoiesis but are also essential for memory T cell maintenance. Consequently, hematopoietic progenitors and differentiated immune cells, such as memory T cell subsets, also depend on the CXCL12/CXCR4 axis for migration into bone marrow and interactions with MSPCs and ECs. Similarly, subsets of antibody-secreting plasma cells also reside in close association with CXCL12-producing MSPCs in the bone marrow and require the CXCR4/CXCL12 axis for survival and long-term maintenance. Collectively, these studies demonstrate a broad range of key physiological roles, spanning blood cell production and maintenance of immunological memory, that are orchestrated by stem cell niches through a common and simple mechanism: CXCL12/CXCR4-mediated cell recruitment followed by receipt of a maintenance and/or instructive signal. A fundamental flaw of this type of cellular organization is revealed by myeloid and lymphoid leukemias, which target stem cell niches and induce profound transcriptomic changes that result in reduced hematopoietic activity and altered mesenchymal cell differentiation.

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Section: Leukemia and Its Impact On Bone Marrow Niches Hematopoiesismentioning

confidence: 99%

Hematopoietic Stem Cell Niches and Signals Controlling Immune Cell Development and Maintenance of Immunological Memory

et al. 2020

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“…The expanding malignant cells not only impairs stromal cells and hematopoiesis, but also remodels BM immune microenvironment [ 3 ]. The malignant myeloid cells can impair osteogenesis [ 4 ], HSC-progenitor transition [ 5 ], myelo-erythropoiesis [ 6 ], erythroid differentiation [ 7 ], macrophage phagocytosis [ 8 ], dendritic cell differentiation [ 9 ], T cell anti-tumor function [ 10 ], and Natural killer (NK) cell immune surveillance [ 11 ]. However, compared with other cancer types, especially solid tumor, the immune cell types, immune status, and molecular mechanisms of AML patient BM microenvironment are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment

et al. 2021

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Background Knowledge of immune cell phenotypes, function, and developmental trajectory in acute myeloid leukemia (AML) microenvironment is essential for understanding mechanisms of evading immune surveillance and immunotherapy response of targeting special microenvironment components. Methods Using a single-cell RNA sequencing (scRNA-seq) dataset, we analyzed the immune cell phenotypes, function, and developmental trajectory of bone marrow (BM) samples from 16 AML patients and 4 healthy donors, but not AML blasts. Results We observed a significant difference between normal and AML BM immune cells. Here, we defined the diversity of dendritic cells (DC) and macrophages in different AML patients. We also identified several unique immune cell types including T helper cell 17 (TH17)-like intermediate population, cytotoxic CD4+ T subset, T cell: erythrocyte complexes, activated regulatory T cells (Treg), and CD8+ memory-like subset. Emerging AML cells remodels the BM immune microenvironment powerfully, leads to immunosuppression by accumulating exhausted/dysfunctional immune effectors, expending immune-activated types, and promoting the formation of suppressive subsets. Conclusion Our results provide a comprehensive AML BM immune cell census, which can help to select pinpoint targeted drug and predict efficacy of immunotherapy.

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“…The role of immune checkpoint inhibition in MDS, acute myeloid leukemia (AML), and other myeloid malignancies is under active clinical investigation [13,[75][76][77]. Although MDS and AML exhibit low neoantigen burden, these malignancies are associated with a markedly exhausted T-cell repertoire; therefore, inhibition of immune checkpoints associated with T-cell exhaustion, such as PD-1, CTLA-4, and TIM-3, may serve to reactivate immune function [78][79][80]. Similarly, T-cell-mediated immune tolerance and increased PD-1 expression have been observed in myelofibrosis [81].…”

Section: Targeting Tim-3 In Myeloid Malignanciesmentioning

confidence: 99%

TIM-3 pathway dysregulation and targeting in cancer

Zeidan

Komrokji

Brunner

2021

Expert Review of Anticancer Therapy

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Introduction: Dysfunction of the immune system is a hallmark of cancer. Through increased understanding of the complex interactions between immunity and cancer, immunotherapy has emerged as a treatment modality for different types of cancer. Promising activity with immunotherapy has been reported in numerous malignancies, but challenges such as limited response rates and treatment resistance remain. Furthermore, outcomes with this therapeutic approach in hematologic malignancies are even more limited than in solid tumors. T-cell immunoglobulin domain and mucin domain 3 (TIM-3) has emerged as a potential immune checkpoint target in both solid tumors and hematologic malignancies. TIM-3 has been shown to promote immune tolerance, and overexpression of TIM-3 is associated with more aggressive or advanced disease and poor prognosis.Areas covered: This review examines what is currently known regarding the biology of TIM-3 and clinical implications of targeting TIM-3 in cancer. Particular focus is given to myeloid malignancies. Expert opinion: The targeting of TIM-3 is a promising therapeutic approach in cancers, including hematologic cancers such as myeloid malignancies which have not benefited much from current immunotherapeutic treatment approaches. We anticipate that with further clinical evaluation, TIM-3 blockade will emerge as an important treatment strategy in myeloid malignancies.

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Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia

Cited by 64 publications

References 79 publications

Hematopoietic Stem Cell Niches and Signals Controlling Immune Cell Development and Maintenance of Immunological Memory

Hematopoietic Stem Cell Niches and Signals Controlling Immune Cell Development and Maintenance of Immunological Memory

Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment

TIM-3 pathway dysregulation and targeting in cancer

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