Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma

Approximately 50% of Merkel cell carcinoma (MCC) patients facing this highly aggressive skin cancer initially respond positively to PD-1-based immunotherapy. Nevertheless, the recurrence of MCC post-immunotherapy emphasizes the pressing need for more effective treatments. Recent research has highlig...

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Vydáno v:Heliyon Ročník 10; číslo 1; s. e23521
Hlavní autoři: Lee, Jung Hyun, Lee, Justin Daho, Paulson, Kelly, Voillet, Valentin, Berndt, Andre, Church, Candice, Lachance, Kristina, Park, Song Y., Yamamoto, Naomi K., Cromwell, Elizabeth A., Gottardo, Raphael, Chapuis, Aude G., Nghiem, Paul
Médium: Journal Article
Jazyk:angličtina
Vydáno: England Elsevier Ltd 15.01.2024
Elsevier
Témata:
carcinoma
CDK4/6 inhibitor
cell cycle
cell death
cyclin-dependent kinase
Hypoxia
Immunogenic cell death
immunotherapy
skin neoplasms
transcription (genetics)
Hypoxia
Immunogenic cell death
CDK4/6 inhibitor
ISSN:2405-8440, 2405-8440
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Shrnutí:Approximately 50% of Merkel cell carcinoma (MCC) patients facing this highly aggressive skin cancer initially respond positively to PD-1-based immunotherapy. Nevertheless, the recurrence of MCC post-immunotherapy emphasizes the pressing need for more effective treatments. Recent research has highlighted Cyclin-dependent kinases 4 and 6 (CDK4/6) as pivotal cell cycle regulators gaining prominence in cancer studies. This study reveals that the CDK4/6 inhibitor, palbociclib can enhance PD-L1 gene transcription and surface expression in MCC cells by activating HIF2α. Inhibiting HIF2α with TC-S7009 effectively counteracts palbociclib-induced PD-L1 transcription and significantly intensifies cell death in MCC. Simultaneously, co-targeting CDK4/6 and HIF2α boosts ROS levels while suppressing SLC7A11, a key regulator of cellular redox balance, promoting ferroptosis- a form of immunogenic cell death linked to iron. Considering the rising importance of immunogenic cell death in immunotherapy, this strategy holds promise for improving future MCC treatments, markedly increasing immunogenic cell death across various MCC cell lines, thus advancing cancer immunotherapy.
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These authors contributed equally to this work.
ISSN:2405-8440
2405-8440
DOI:10.1016/j.heliyon.2023.e23521