Conventional amphotericin B elicits markers of immunogenic cell death on leukemic blasts, mediates immunostimulatory effects on phagocytic cells, and synergizes with PD-L1 blockade.
Amphotericin B
ICD
PD-L1
calreticulin
immunomodulatory therapy
Journal
Oncoimmunology
ISSN: 2162-402X
Titre abrégé: Oncoimmunology
Pays: United States
ID NLM: 101570526
Informations de publication
Date de publication:
2022
2022
Historique:
entrez:
2
5
2022
pubmed:
3
5
2022
medline:
4
5
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35496500
doi: 10.1080/2162402X.2022.2068109
pii: 2068109
pmc: PMC9045824
doi:
Substances chimiques
B7-H1 Antigen
0
Biomarkers
0
Amphotericin B
7XU7A7DROE
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2068109Informations de copyright
© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.
Déclaration de conflit d'intérêts
No potential conflict of interest was reported by the author(s).
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