Amphotericin B, an Anti-Fungal Medication, Directly Increases the Cytotoxicity of NK Cells

Kim, Nayoung; Choi, Jin-Won; Park, Hye-Ran; Kim, Inki; Kim, Hun Sik

doi:10.3390/ijms18061262

Cited by 10 publications

(5 citation statements)

References 35 publications

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“…AmB is not only a TLR2 and TLR4 agonist, 43 that directly enhances NK cell cytotoxicity. 44 It can increase autophagic activity, 28 and has immunomodulatory effects. It affects both ATP-secretion and IFN-1ß-production, 23 , 29 and influences the so-called type I interferon signature, 45 processes that are also associated with ICD.…”

Section: Discussionmentioning

confidence: 99%

Conventional amphotericin B elicits markers of immunogenic cell death on leukemic blasts, mediates immunostimulatory effects on phagocytic cells, and synergizes with PD-L1 blockade

et al. 2022

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Immunostimulatory regimens are a game changer in the fight against cancer, but still only a minority of patients achieve clinical benefit. Combination with immunomodulatory drugs and agents converting otherwise non-immunogenic forms of cell death into bona fide “immunogenic cell death” (ICD) could improve the efficacy of these novel therapies. The aim of our study was to investigate conventional Amphotericin B (AmB) as an enhancer of antitumor immune responses. In tumor cell line models, AmB induced ICD with its typical hallmarks of calreticulin (CALR) expression and release of high mobility group box 1 (HMGB1) as well as Adenosine 5’-triphosphate (ATP). Interestingly, in contrast to non-ICD inducing treatments, ICD induction led to up-regulation of PD-L1-expression by ICD experiencing cells, resulting in decreased maturation of dendritic cells (DCs). Blocking this PD-L1 expression on tumor cells could unleash full ICD effects on antigen presenting cells. Even at sub-toxic concentrations, AmB was able to enhance CALR on leukemic blasts, particularly on phagocytic monoblastic THP-1 cells, which also showed features of “M1-like” differentiation after AmB exposure. The ability of AmB to increase the immunogenicity of tumor cells was confirmed in vivo in a mouse vaccination experiment. In conclusion, we demonstrate that AmB can promote antitumor immune responses in a dose-dependent manner by ICD induction, surface translocation of CALR on leukemic blasts even at sub-toxic concentrations, and “M1-like” polarization of phagocytic cells, making it noteworthy as potential booster for cancer immunotherapy. We additionally report for the first time that PD-L1 expression may be a feature of ICD, possibly as a negative feedback mechanism regulating the maturation status of DCs and thus indirectly affecting T-cell priming.

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Section: Discussionmentioning

confidence: 99%

Conventional amphotericin B elicits markers of immunogenic cell death on leukemic blasts, mediates immunostimulatory effects on phagocytic cells, and synergizes with PD-L1 blockade

et al. 2022

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“…However, even in light of these limitations, the screening identified compounds previously reported to enhance NK cell activity, including amphotericin B [ 19 ]. We also identified nicotinamide, which is currently under investigation in clinical trials as a supportive agent for the ex vivo expansion of primary NK cells for the treatment of Non-Hodgkin lymphoma and multiple myeloma [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have conducted high-throughput drug screenings to identify drugs that modulate NK cell activity. These studies utilized commercially available libraries containing repurposed drugs [ 18 , 19 , 20 ] or natural compound libraries [ 21 , 22 ] and have identified small molecules that were not previously known to modulate NK cell activity. Here, we screened the Prestwick Chemical Library for compounds capable of enhancing the cytotoxicity of human NK cells towards leukemia target cells and identified the antibiotic colistin sulfate as an enhancer of NK cell cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

A New Functional Screening Platform Identifies Colistin Sulfate as an Enhancer of Natural Killer Cell Cytotoxicity

Cortés-Kaplan

Kurdieh

Hasim

et al. 2022

Cancers

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Due to their crucial role in tumor immunity, NK cells have quickly became a prime target for immunotherapies, with the adoptive transfer of NK cells and the use of NK cell engagers quickly moving to the clinical stage. On the other hand, only a few studies have focused on small molecule drugs capable of unleashing NK cells against cancer. In this context, repurposing small molecules is an attractive strategy to identify new immunotherapies from already approved drugs. Here, we developed a new platform to screen small molecule compounds based on a high-throughput luciferase-release cytotoxicity assay. We tested 1200 FDA approved drugs from the Prestwick Chemical Library, to identify compounds that increase NK cells’ cytotoxic potential. We found that the antibiotic colistin sulfate increased the cytotoxicity of human NK cells towards cancer cells. The effect of colistin was short lived and was not observed when NK cells were pretreated with the drug, showing how NK cell activity was potentiated only when the compound was present at the time of recognition of cancer cells. Further studies are needed to uncover the mechanism of action and the pre-clinical efficacy of colistin sulfate in mouse cancer models.

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“…However, even in light of these limitations, the screening identified compounds previously reported to enhance NK cell activity, including amphotericin B 19 . We also identified nicotinamide, which is currently under investigation in clinical trials as a supportive agent for ex vivo expansion of primary NK cells for the treatment of Non-Hodgkin lymphoma and multiple myeloma 27 .…”

Section: Discussionmentioning

confidence: 99%

A small molecule drug screening identifies colistin sulfate as an enhancer of Natural Killer cell cytotoxicity

Cortés-Kaplan

Hasim

Kaczmarek

et al. 2021

Preprint

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Because of their crucial role in tumor immunity, NK cells have quickly become a prime target for immunotherapies, with adoptive transfer of NK cells and the use of NK cell engagers quickly moving to clinical stage. On the other hand, only few studies have focused on small molecule drugs capable of unleashing NK cell against cancer. In this context, repurposing small molecule is an attractive strategy to identify new immunotherapies from already approved drugs. Here, we screened 1,200 FDA-approved drugs from the Prestwick Chemical Library, to identify compounds that increase NK cell cytotoxic potential. Using a high-throughput luciferase-release cytotoxicity assay, we found that the antibiotic colistin sulfate increased cytotoxicity of human NK cells towards cancer cells. The effect of colistin was short lived and was not observed when NK cells were pretreated with the drug, showing how NK cell activity was potentiated only when the compound was present at the time of recognition of cancer cells. Further studies are needed to uncover the mechanism of action and the pre-clinical efficacy of colistin sulfate in mouse cancer models.

show abstract

Amphotericin B, an Anti-Fungal Medication, Directly Increases the Cytotoxicity of NK Cells

Cited by 10 publications

References 35 publications

Conventional amphotericin B elicits markers of immunogenic cell death on leukemic blasts, mediates immunostimulatory effects on phagocytic cells, and synergizes with PD-L1 blockade

Conventional amphotericin B elicits markers of immunogenic cell death on leukemic blasts, mediates immunostimulatory effects on phagocytic cells, and synergizes with PD-L1 blockade

A New Functional Screening Platform Identifies Colistin Sulfate as an Enhancer of Natural Killer Cell Cytotoxicity

A small molecule drug screening identifies colistin sulfate as an enhancer of Natural Killer cell cytotoxicity

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