6 results on '"Murphy, Maureen E."'
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2. Fatty acid transporter 2 reprograms neutrophils in cancer
- Author
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Veglia, Filippo, Tyurin, Vladimir A., Blasi, Maria, De Leo, Alessandra, Kossenkov, Andrew, Donthireddy, Laxminarasimha, Jerrick, To Tsun Ki, Schug, Zach, Basu, Subhasree, Wang, Fang, Ricciotti, Emanuela, DiRusso, Concetta, Murphy, Maureen E., Vonderheide, Robert H., Lieberman, Paul M., Mulligan, Charles, Nam, Brian, Hockstein, Neil, Masters, Gregory, Guarino, Michael, Lin, Cindy, Nefedova, Yulia, Black, Paul, Kagan, Valerian E., and Gabrilovich, Dmitry
- Subjects
Neutrophils ,Neoplasms ,Fatty Acids ,Humans ,Fatty Acid Transport Proteins ,Article - Abstract
Summary Polymorphonuclear myeloid derived suppressor cells (PMN-MDSC) are pathologically activated neutrophils that are critically important for the regulation of immune responses in cancer. They contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite the recent advances in understanding of the PMN-MDSC biology, the mechanisms responsible for pathological activation of neutrophils are not well defined, which limits selective targeting of these cells. Here, we report that mouse and human PMN-MDSC exclusively up-regulate fatty acid transporter protein 2 (FATP2). Over-expression of FATP2 in PMN-MDSC was controlled by GM-CSF, through the activation of STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSC. The main mechanism of FATP2 mediated suppressive activity involved uptake of arachidonic acid (AA) and synthesis of prostaglandin E2 (PGE2). The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSC and substantially delayed tumor progression. In combination with check-point inhibitors it blocked tumor progression in mice. Thus, FATP2 mediates acquisition of immune suppressive activity by PMN-MDSC and represents a new target to selectively inhibit the functions of PMN-MDSC and improve the effect of cancer therapy.
- Published
- 2019
3. RETRACTED ARTICLE: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance
- Author
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Singh, Kumar Sachin, primary, Sharma, Rishabh, additional, Reddy, Poli Adi Narayana, additional, Vonteddu, Prashanthi, additional, Good, Madeline, additional, Sundarrajan, Anjana, additional, Choi, Hyeree, additional, Muthumani, Kar, additional, Kossenkov, Andrew, additional, Goldman, Aaron R., additional, Tang, Hsin-Yao, additional, Totrov, Maxim, additional, Cassel, Joel, additional, Murphy, Maureen E., additional, Somasundaram, Rajasekharan, additional, Herlyn, Meenhard, additional, Salvino, Joseph M., additional, and Dotiwala, Farokh, additional
- Published
- 2020
- Full Text
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4. Fatty acid transport protein 2 reprograms neutrophils in cancer
- Author
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Veglia, Filippo, primary, Tyurin, Vladimir A., additional, Blasi, Maria, additional, De Leo, Alessandra, additional, Kossenkov, Andrew V., additional, Donthireddy, Laxminarasimha, additional, To, Tsun Ki Jerrick, additional, Schug, Zach, additional, Basu, Subhasree, additional, Wang, Fang, additional, Ricciotti, Emanuela, additional, DiRusso, Concetta, additional, Murphy, Maureen E., additional, Vonderheide, Robert H., additional, Lieberman, Paul M., additional, Mulligan, Charles, additional, Nam, Brian, additional, Hockstein, Neil, additional, Masters, Gregory, additional, Guarino, Michael, additional, Lin, Cindy, additional, Nefedova, Yulia, additional, Black, Paul, additional, Kagan, Valerian E., additional, and Gabrilovich, Dmitry I., additional
- Published
- 2019
- Full Text
- View/download PDF
5. IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance.
- Author
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Singh, Kumar Sachin, Sharma, Rishabh, Reddy, Poli Adi Narayana, Vonteddu, Prashanthi, Good, Madeline, Sundarrajan, Anjana, Choi, Hyeree, Muthumani, Kar, Kossenkov, Andrew, Goldman, Aaron R., Tang, Hsin-Yao, Totrov, Maxim, Cassel, Joel, Murphy, Maureen E., Somasundaram, Rajasekharan, Herlyn, Meenhard, Salvino, Joseph M., and Dotiwala, Farokh
- Abstract
Isoprenoids are vital for all organisms, in which they maintain membrane stability and support core functions such as respiration1. IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential for Gram-negative bacteria, mycobacteria and apicomplexans2,3. Its substrate, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), is not produced in metazoans, and in humans and other primates it activates cytotoxic Vγ9Vδ2 T cells at extremely low concentrations4–6. Here we describe a class of IspH inhibitors and refine their potency to nanomolar levels through structure-guided analogue design. After modification of these compounds into prodrugs for delivery into bacteria, we show that they kill clinical isolates of several multidrug-resistant bacteria—including those from the genera Acinetobacter, Pseudomonas, Klebsiella, Enterobacter, Vibrio, Shigella, Salmonella, Yersinia, Mycobacterium and Bacillus—yet are relatively non-toxic to mammalian cells. Proteomic analysis reveals that bacteria treated with these prodrugs resemble those after conditional IspH knockdown. Notably, these prodrugs also induce the expansion and activation of human Vγ9Vδ2 T cells in a humanized mouse model of bacterial infection. The prodrugs we describe here synergize the direct killing of bacteria with a simultaneous rapid immune response by cytotoxic γδ T cells, which may limit the increase of antibiotic-resistant bacterial populations. A class of compounds with a dual mechanism of action—direct targeting of IspH and stimulation of cytotoxic γδ T cells to enhance pathogen clearance—are active against multidrug-resistant bacteria. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
6. RETRACTED ARTICLE: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance
- Author
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Singh, Kumar Sachin, Sharma, Rishabh, Reddy, Poli Adi Narayana, Vonteddu, Prashanthi, Good, Madeline, Sundarrajan, Anjana, Choi, Hyeree, Muthumani, Kar, Kossenkov, Andrew, Goldman, Aaron R., Tang, Hsin-Yao, Totrov, Maxim, Cassel, Joel, Murphy, Maureen E., Somasundaram, Rajasekharan, Herlyn, Meenhard, Salvino, Joseph M., and Dotiwala, Farokh
- Abstract
Isoprenoids are vital for all organisms, in which they maintain membrane stability and support core functions such as respiration1. IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential for Gram-negative bacteria, mycobacteria and apicomplexans2,3. Its substrate, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), is not produced in metazoans, and in humans and other primates it activates cytotoxic Vγ9Vδ2 T cells at extremely low concentrations4–6. Here we describe a class of IspH inhibitors and refine their potency to nanomolar levels through structure-guided analogue design. After modification of these compounds into prodrugs for delivery into bacteria, we show that they kill clinical isolates of several multidrug-resistant bacteria—including those from the genera Acinetobacter, Pseudomonas, Klebsiella, Enterobacter, Vibrio, Shigella, Salmonella, Yersinia, Mycobacteriumand Bacillus—yet are relatively non-toxic to mammalian cells. Proteomic analysis reveals that bacteria treated with these prodrugs resemble those after conditional IspH knockdown. Notably, these prodrugs also induce the expansion and activation of human Vγ9Vδ2 T cells in a humanized mouse model of bacterial infection. The prodrugs we describe here synergize the direct killing of bacteria with a simultaneous rapid immune response by cytotoxic γδ T cells, which may limit the increase of antibiotic-resistant bacterial populations.
- Published
- 2021
- Full Text
- View/download PDF
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