Acute myeloid leukemia–induced T-cell suppression can be reversed by inhibition of the MAPK pathway

Moshofsky, Kaycee B.; Cho, Hyun J.; Wu, Guanming; Romine, Kyle A.; Newman, Matthew T.; Kosaka, Yoko; McWeeney, Shannon K.; Lind, Evan F.

doi:10.1182/bloodadvances.2019000574

Cited by 15 publications

(18 citation statements)

References 54 publications

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“…More recent evidence shows that high expression of PD-L1 on AML cells is associated with worse overall survival in patients with FLT3-ITD and NPM1 mutations [ 60 ]. Several studies highlighted induction of PD-L1 expression after treatment with interferons [ 61 , 62 ], while reduced expression of PD-L1 was observed on AML cells in patients after treatment with mitogen activated protein kinase kinase (MEK) inhibitors [ 61 , 63 ]. Additionally, signal transducer and activator of transcription 3 (STAT3) inhibition in AML mouse model resulted in downregulation of PD-L1 and induction of anti-leukemic immune response [ 64 ].…”

Section: Leukemia-derived Factors That Promote Immune Evasionmentioning

confidence: 99%

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Swatler

Turos-Korgul

Kozłowska

et al. 2021

Cancers

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Both chronic myeloid leukemia and acute myeloid leukemia evade the immune response during their development and disease progression. As myeloid leukemia cells modify their bone marrow microenvironment, they lead to dysfunction of cytotoxic cells, such as CD8+ T cells or NK cells, simultaneously promoting development of immunosuppressive regulatory T cells and suppressive myeloid cells. This facilitates disease progression, spreading of leukemic blasts outside the bone marrow niche and therapy resistance. The following review focuses on main immunosuppressive features of myeloid leukemias. Firstly, factors derived directly from leukemic cells – inhibitory receptors, soluble factors and extracellular vesicles, are described. Further, we outline function, properties and origin of main immunosuppressive cells - regulatory T cells, myeloid derived suppressor cells and macrophages. Finally, we analyze interplay between recovery of effector immunity and therapeutic modalities, such as tyrosine kinase inhibitors and chemotherapy.

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Section: Leukemia-derived Factors That Promote Immune Evasionmentioning

confidence: 99%

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Swatler

Turos-Korgul

Kozłowska

et al. 2021

Cancers

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“…We previously showed that our genetically-engineered mouse model, FLT3-ITD +/- TET2 flox/+ LysM-Cre +/- displays a profound defect in T cell proliferative capacity 44 . To further characterize the tumor microenvironment and functional capacity of T cells derived from this mouse model, we performed multi-color flow cytometry to immunophenotype myeloid and lymphoid population and histology of multiple organ sites.…”

Section: Resultsmentioning

confidence: 89%

BET inhibitors synergize with anti-PD1 by rescuing TCF1⁺ progenitor exhausted CD8⁺ T cells in Acute Myeloid Leukemia

Romine

Cho

Kosaka

et al. 2021

Preprint

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Many AML patients exhibit hallmarks of immune exhaustion such as increased myeloid derived suppressor cells (MDSCs), suppressive regulatory T cells (Tregs), and exhausted/dysfunctional T cells. We developed an AML mouse model driven by FLT3-ITD and TET2 deficiency to evaluate the immune effects of small-molecule inhibitors (SMIs) and immune checkpoint blockade (ICB). This mouse model recapitulated immune-related features in AML patients, such as increased myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Moreover, we found that CD8+ T cells derived from these mice exhibit a terminally exhausted phenotype (TEx PD1+, TIM3+, TCF1-), which have been shown to be refractory to ICB monotherapy. Here we show that SMIs targeting Bromodomain and Extra-Terminal (BET) proteins, in addition to targeting tumor-intrinsic factors, rescue T cell exhaustion and ICB resistance. Ex vivo treatment of splenocytes from these mice with BET inhibitors (BETi) reversed CD8+ T cell exhaustion by restoring proliferative capacity and expanding the more functional precursor exhausted T cells (TPEx: PD1+, TCF1+, TIM3-). This reversal is even more pronounced with BETi in combination with anti-PD1. Finally, we show that BETi synergizes with anti-PD1 in vivo, resulting in the reduction of circulating leukemia cells, enrichment of CD8+ T cells in the bone marrow and increased TPEx CD8+ T cells. In total, we employ an AML mouse model that is characterized by leukemia-induced immune exhaustion to show the potential efficacy of combining BETi and ICB therapy in the treatment of AML.

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“…CREB binding protein (CREBBP) is an important protein for the autonomous cellular regulation of hematopoiesis, including the stem cell [ 71 ]. For example, it is known that the bone marrow microenvironment is suppressive for the active cells of the immune system, therefore promoting the leukemic clone progression [ 72 , 73 , 74 ]. Regulatory T-cells have been identified for being used by leukemic cells to evade the immune response.…”

Section: Discussionmentioning

confidence: 99%

“…Regulatory T-cells have been identified for being used by leukemic cells to evade the immune response. In addition, the protective effects of the marrow achieve protection against cytotoxic drugs, allowing the development of cell resistance that imposes the need for the development of appropriate drugs and the microenvironment [ 72 , 73 , 74 ].…”

Section: Discussionmentioning

confidence: 99%

Dual Mechanisms of Metabolism and Gene Expression of the CCRF-CEM Leukemia Cells under Glucocorticoid Treatment

Lambrou

Karakonstantakis

Vlahopoulos

et al. 2021

IJMS

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Background: Glucocorticoids play an essential part in anti-leukemic therapies, but resistance is a crucial event for the prognosis of the disease. Glucocorticoids influence the metabolic properties of leukemic cells. The inherent plasticity of clinically evolving cancer cells justifies the characterization of drug-induced early oncogenic pathways, which represent a likely source of detrimental secondary effects. Aim: The present work aims to investigate the effect of glucocorticoids in metabolic pathways in the CCRF-CEM leukemic cells. Metabolic factors and gene expression profiles were examined in order to unravel the possible mechanisms of the CCRF-CEM leukemic cell growth dynamics. Methods: CCRF-CEM cells were used as a model. Cells were treated with prednisolone with concentrations 0–700 μM. Cell culture supernatants were used for glucose, lactic acid, LDH, Na+, K+ and Ca++ measurements. Cytotoxicity was determined with flow cytometry. Microarray analysis was performed using two different chips of 1.2 k and 4.8 k genes. Gene Ontology enrichment analysis was applied to find metabolism- and GC-related genes. Results: Higher prednisolone concentrations inhibited glucose uptake, without exhibiting any cytotoxic effects. Glucose consumption did not correlate with the total cell population, or the viable population, indicating that growth is not directly proportional to glucose consumption. Neither of the subpopulations, i.e., viable, necrotic, or apoptotic cells, contributed to this. Conclusions: Different types of leukemic cells seem to exhibit different patterns of glucose metabolism. Both resistant and sensitive CCRF-CEM cells followed the aerobic pathway of glycolysis. There is probably a rapid change in membrane permeability, causing a general shutdown towards everything that is outside the cell. This could in part also explain the observed resistance. Glucocorticoids do not enter the cell passively anymore and therefore no effects are observed. Based on our observations, ion concentrations are measurable factors both in vitro and in vivo, which makes them possible markers of glucocorticoid cytotoxic action.

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Acute myeloid leukemia–induced T-cell suppression can be reversed by inhibition of the MAPK pathway

Abstract: Key Points MEK inhibition rescues T cells from activation-induced cell death in an AML model. MEK inhibitor sensitivity is associated with inflammation pathways and PD-L1 expression.

Cited by 15 publications

References 54 publications

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

BET inhibitors synergize with anti-PD1 by rescuing TCF1⁺ progenitor exhausted CD8⁺ T cells in Acute Myeloid Leukemia

Dual Mechanisms of Metabolism and Gene Expression of the CCRF-CEM Leukemia Cells under Glucocorticoid Treatment

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Acute myeloid leukemia–induced T-cell suppression can be reversed by inhibition of the MAPK pathway

Abstract: Key Points MEK inhibition rescues T cells from activation-induced cell death in an AML model. MEK inhibitor sensitivity is associated with inflammation pathways and PD-L1 expression.

Cited by 15 publications

References 54 publications

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

BET inhibitors synergize with anti-PD1 by rescuing TCF1+ progenitor exhausted CD8+ T cells in Acute Myeloid Leukemia

Dual Mechanisms of Metabolism and Gene Expression of the CCRF-CEM Leukemia Cells under Glucocorticoid Treatment

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BET inhibitors synergize with anti-PD1 by rescuing TCF1⁺ progenitor exhausted CD8⁺ T cells in Acute Myeloid Leukemia