4 results on '"Ashly Sanchez Ortiz"'
Search Results
2. Intrinsic suppression of type I interferon production underlies the therapeutic efficacy of IL-15-producing natural killer cells in B-cell acute lymphoblastic leukemia
- Author
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Anil Kumar, Min Huang, Norman J. Lacayo, Holden T. Maecker, Stephen J. Forman, Srividya Swaminathan, Caroline Duault, Jianhua Yu, Steven T. Rosen, Anthony Chan, Martin Carroll, Adeleh Taghi Khani, Soraya Aramburo, Ashly Sanchez Ortiz, Sung June Lee, Tinisha McDonald, Kathleen M. Sakamoto, Christian Hurtz, Sarah K. Tasian, Lucy Ghoda, Guido Marcucci, Zhaohui Gu, Saro Armenian, Shai Izraeli, Chun-Wei Chen, and Michael A. Caligiuri
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Type I interferons (IFN-Is), secreted by hematopoietic cells, drive immune surveillance of solid tumors. However, the mechanisms of suppression of IFN-I-driven immune responses in hematopoietic malignancies including B-cell acute lymphoblastic leukemia (B-ALL) are unknown.Methods Using high-dimensional cytometry, we delineate the defects in IFN-I production and IFN-I-driven immune responses in high-grade primary human and mouse B-ALLs. We develop natural killer (NK) cells as therapies to counter the intrinsic suppression of IFN-I production in B-ALL.Results We find that high expression of IFN-I signaling genes predicts favorable clinical outcome in patients with B-ALL, underscoring the importance of the IFN-I pathway in this malignancy. We show that human and mouse B-ALL microenvironments harbor an intrinsic defect in paracrine (plasmacytoid dendritic cell) and/or autocrine (B-cell) IFN-I production and IFN-I-driven immune responses. Reduced IFN-I production is sufficient for suppressing the immune system and promoting leukemia development in mice prone to MYC-driven B-ALL. Among anti-leukemia immune subsets, suppression of IFN-I production most markedly lowers the transcription of IL-15 and reduces NK-cell number and effector maturation in B-ALL microenvironments. Adoptive transfer of healthy NK cells significantly prolongs survival of overt ALL-bearing transgenic mice. Administration of IFN-Is to B-ALL-prone mice reduces leukemia progression and increases the frequencies of total NK and NK-cell effectors in circulation. Ex vivo treatment of malignant and non-malignant immune cells in primary mouse B-ALL microenvironments with IFN-Is fully restores proximal IFN-I signaling and partially restores IL-15 production. In B-ALL patients, the suppression of IL-15 is the most severe in difficult-to-treat subtypes with MYC overexpression. MYC overexpression promotes sensitivity of B-ALL to NK cell-mediated killing. To counter the suppressed IFN-I-induced IL-15 production in MYChigh human B-ALL, we CRISPRa-engineered a novel human NK-cell line that secretes IL-15. CRISPRa IL-15-secreting human NK cells kill high-grade human B-ALL in vitro and block leukemia progression in vivo more effectively than NK cells that do not produce IL-15.Conclusion We find that restoration of the intrinsically suppressed IFN-I production in B-ALL underlies the therapeutic efficacy of IL-15-producing NK cells and that such NK cells represent an attractive therapeutic solution for the problem of drugging MYC in high-grade B-ALL.
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- 2023
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3. GM-CSF: A Double-Edged Sword in Cancer Immunotherapy
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Anil Kumar, Adeleh Taghi Khani, Ashly Sanchez Ortiz, and Srividya Swaminathan
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GM-CSF (granulocyte-macrophage colony-stimulating factor) ,tumor immune microenvironment ,cancer treatment ,anti-tumor cytokines ,pro-tumor cytokines ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that drives the generation of myeloid cell subsets including neutrophils, monocytes, macrophages, and dendritic cells in response to stress, infections, and cancers. By modulating the functions of innate immune cells that serve as a bridge to activate adaptive immune responses, GM-CSF globally impacts host immune surveillance under pathologic conditions. As with other soluble mediators of immunity, too much or too little GM-CSF has been found to promote cancer aggressiveness. While too little GM-CSF prevents the appropriate production of innate immune cells and subsequent activation of adaptive anti-cancer immune responses, too much of GM-CSF can exhaust immune cells and promote cancer growth. The consequences of GM-CSF signaling in cancer progression are a function of the levels of GM-CSF, the cancer type, and the tumor microenvironment. In this review, we first discuss the secretion of GM-CSF, signaling downstream of the GM-CSF receptor, and GM-CSF’s role in modulating myeloid cell homeostasis. We then outline GM-CSF’s anti-tumorigenic and pro-tumorigenic effects both on the malignant cells and on the non-malignant immune and other cells in the tumor microenvironment. We provide examples of current clinical and preclinical strategies that harness GM-CSF’s anti-cancer potential while minimizing its deleterious effects. We describe the challenges in achieving the Goldilocks effect during administration of GM-CSF-based therapies to patients with cancer. Finally, we provide insights into how technologies that map the immune microenvironment spatially and temporally may be leveraged to intelligently harness GM-CSF for treatment of malignancies.
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- 2022
- Full Text
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4. Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms
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Adeleh Taghi Khani, Anil Kumar, Ashly Sanchez Ortiz, Kelly Radecki, Sung June Lee, Zunsong Hu, Behzad Damirchi, Mary Lorenson, Xiwei Wu, Zhaohui Gu, William Stohl, Ignacio Sanz, Eric Meffre, Markus Müschen, Stephen Forman, Jean Koff, Ameae Walker, and Srividya Swaminathan
- Abstract
Prolactin (PRL) is elevated in B-cell mediated lymphoproliferative diseases and promotes B-cell survival. However, whether PRL or PRL receptors drive the initiation, establishment, and sustenance of B-cell malignancies is unknown. We measured changes in B cells after knocking down the pro-proliferative, anti-apoptotic long isoform of the PRL receptor (LFPRLR) in vivo in systemic lupus erythematosus (SLE)- and B-cell lymphoma-prone mouse models, and the LFPRLR plus intermediate isoforms (LF/IFPRLR) in vitro in malignant human B cells. To knockdown LF/IFPRLRs without suppressing expression of the counteractive short PRLR isoforms (SFPRLRs), we employed splice-modulating DNA oligomers. In SLE-prone mice, LFPRLR knockdown reduced numbers and proliferation of B-cell subsets and lowered the risk of B-cell transformation by downregulating expression of activation-induced cytidine deaminase. LFPRLR knockdown in lymphoma-prone mice reduced B-cell numbers and their expression of BCL2. In overt human B-cell malignancies, LF/IFPRLR knockdown reduced B-cell viability and their MYC and BCL2 expression. Unlike their normal counterparts which produced no autocrine PRL and expressed SFPRLRs, malignant human B cells expressed autocrine PRL and often no SFPRLRs. Isoform-specific knockdown of the LF/IFPRLR was not toxic to mice or to normal human immune cells, suggesting it is a safe approach to block the evolution of B-cell malignancies.
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- 2022
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