BH3 Mimetics Augment Cytotoxic T Cell Killing of Acute Myeloid Leukemia via Mitochondrial Apoptotic Mechanism
Cassian YeeKapil SaxenaEsther RyuShao-Hsi HungShailbala SinghQi ZhangZhihong ZengZhe WangMarina Konopleva
0
Citation
93
Reference
10
Related Paper
Abstract:
Adoptive cell therapy (ACT) can address an unmet clinical need for patients with relapsed/refractory acute myeloid leukemia (AML), but its effect is often modest in the setting of high tumor burden. In this study, we postulated that strategies to lower the AML apoptotic threshold will augment T cell killing of AML cells. BH3 mimetics, such as venetoclax, are a clinically approved class of compounds that predispose cells to intrinsic apoptosis by inhibiting anti-apoptotic mitochondrial proteins. We explored the anti-leukemic efficacy of BH3 mimetics combined with WT1-specific CD8 + T cells on AML cell lines and primary samples from patients with a diverse array of disease characteristics to evaluate if lowering the cellular apoptotic threshold via inhibition of anti-apoptotic mitochondrial proteins can increase leukemic cell sensitivity to T cell therapy. We found that the combination approach of BH3 mimetic and CD8 + T cells led to significantly increased killing of established AML lines as well as of adverse-risk primary AML leukemic blast cells. In contrast to the hypothesis that enhanced killing would be due to combined activation of the intrinsic and extrinsic apoptotic pathways, we found that CTL-mediated killing of AML cells was accomplished primarily through activation of the intrinsic/mitochondrial apoptotic pathway. This highly effective combinatorial activity due to convergence on the same apoptotic pathway was conserved across multiple AML cell lines and primary samples, suggesting that mitochondrial priming may represent a novel mechanism of optimizing adoptive cell therapy for AML patients.Keywords:
Augment
Decreased levels of neutrophils, Fc- and C3-expressing receptors, oxygen-dependent metabolism as well as antibody-dependent cytotoxicity of these cells to target cells were identified in advanced chronic myeloid leukemia, particularly, in blast crisis. Treatment with cytostatic agents resulted in further decrease in said parameters. However, treatment with prodigiozan was followed by improvement in cell functioning.
Cite
Citations (0)
Rosette (schizont appearance)
Fc receptor
Rosette formation
Cell surface receptor
Myeloid leukaemia
Cite
Citations (3)
This chapter describes the myeloid cells of the peripheral blood: neutrophils, eosinophils, basophils, and monocytes. It describes their basic physiology and important disease states associated with defects of each of these entities. Each of these cells arise from a common bone marrow myeloid progenitor to differentiate into their unique types.
Myelopoiesis
Cite
Citations (0)
Abstract Aging, and age-related physiological changes, have been heavily implicated in declining immune functions. Many of these changes to the immune system include changes to the myeloid subsets, which have been poorly studied so far. Myeloid cells play crucial roles in acute infection and are involved in antigen presentation to cells of the adaptive immune system. Consequently, deciphering these age-related mechanisms holds great potential for targeting age-related changes in immunity. Here, we developed a model to map age related phenotypic changes in the myeloid compartment in all immunologically relevant murine organs. Using mass cytometry analysis (CyTOF), we assessed over 35 cell surface parameters on myeloid cells using a geriatric healthy mouse model. Results indicates age-related changes affecting the frequency and cell surface density of lineage markers on myeloid cells. Concretely, we see significant changes to cellular frequencies and marker expression within various resident myeloid populations, and exemplar organs will be presented here. Such age-related patterns may contribute to the impaired immune decline observed in aging. We are currently continually expanding this study and will validate the implications of these findings using spectral flow cytometry analysis.
Mass cytometry
Immunosenescence
Compartment (ship)
Cite
Citations (0)
The tumor microenvironment (TME) of diverse cancer types is often characterized by high levels of infiltrating myeloid cells including monocytes, macrophages, dendritic cells, and granulocytes. These cells perform a variety of functions in the TME, varying from of immune suppressive to immune stimulatory roles. In this review, we summarize the different myeloid cell populations in the TME and the intratumoral myeloid targeting approaches that are being clinically investigated, and discuss strategies that identify new myeloid subpopulations within the TME. The TME therapies include agents that modulate the functional activities of myeloid populations, that impact recruitment and survival of myeloid subpopulations, and that functionally reprogram or activate myeloid populations. We discuss the benefits, limitations and potential side effects of these therapeutic approaches.
Cite
Citations (107)
Both acute myeloid leukemia 1 and c‐Fos are regulatory factors of hematopoietic cell differentiation. We identified that the c‐fos promoter contains an acute myeloid leukemia 1 binding site at nucleotide positions −6–+14. c‐fos promoter activity was induced by transient overexpression of acute myeloid leukemia 1 in Jurkat T‐cells, but not by that of the short form of acute myeloid leukemia 1‐MTG8, a chimeric acute myeloid leukemia 1 protein. In 32Dcl3 myeloid cells, stable overexpression of acute myeloid leukemia 1‐MTG8 blocked the c‐fos gene transcription and cell differentiation, but that of acute myeloid leukemia did not. These data suggest that acute myeloid leukemia 1 and acute myeloid leukemia 1‐MTG8 reciprocally regulate the myeloid cell differentiation, possibly by the way of regulating c‐fos gene transcription.
RUNX1T1
IRF8
Cite
Citations (14)
CD47
Cite
Citations (407)
Recent evidence suggests that myeloid cells are critical in cancer development and therapy resistance processes. Pharmacological targeting of tumor-associated myeloid cells is an emerging approach among upcoming immune therapies. Surprisingly, myeloid cells are heterogeneous, including a subset of the myeloid cell displaying angiogenic properties in solid tumors. There is an urgent need to delineate angiogenic myeloid cell populations in order to facilitate specific targeting of protumor myeloid cells among heterogeneous pool. This review article is intended to compile all the relevant information in the literature for improved understanding of angiogenic myeloid cells and their role in tumor refractoriness to cancer therapy.
Cite
Citations (13)
Cite
Citations (24)