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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Heliyon |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844023107298 |
| _version_ | 1797337032867971072 |
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| author | Jung Hyun Lee Justin Daho Lee Kelly Paulson Valentin Voillet Andre Berndt Candice Church Kristina Lachance Song Y. Park Naomi K. Yamamoto Elizabeth A. Cromwell Raphael Gottardo Aude G. Chapuis Paul Nghiem |
| author_facet | Jung Hyun Lee Justin Daho Lee Kelly Paulson Valentin Voillet Andre Berndt Candice Church Kristina Lachance Song Y. Park Naomi K. Yamamoto Elizabeth A. Cromwell Raphael Gottardo Aude G. Chapuis Paul Nghiem |
| author_sort | Jung Hyun Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T09:03:31Z |
| format | Article |
| id | doaj.art-6b3e03a0dc0c42df8e077d2b0c8553fb |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-03-08T09:03:31Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-6b3e03a0dc0c42df8e077d2b0c8553fb2024-02-01T06:32:16ZengElsevierHeliyon2405-84402024-01-01101e23521Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinomaJung Hyun Lee0Justin Daho Lee1Kelly Paulson2Valentin Voillet3Andre Berndt4Candice Church5Kristina Lachance6Song Y. Park7Naomi K. Yamamoto8Elizabeth A. Cromwell9Raphael Gottardo10Aude G. Chapuis11Paul Nghiem12Department of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA; Corresponding author. Department of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA.Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USADepartment of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Seattle Cancer Care Alliance, Seattle, WA, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USAInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USADepartment of Dermatology, School of Medicine, University of Washington, Seattle, WA, USADepartment of Dermatology, School of Medicine, University of Washington, Seattle, WA, USADepartment of Dermatology, School of Medicine, University of Washington, Seattle, WA, USAMedical Scientist Training Program, University of Washington, Seattle, WA, USASeattle Cancer Care Alliance, Seattle, WA, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USADepartment of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA; Seattle Cancer Care Alliance, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USADepartment of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA; Seattle Cancer Care Alliance, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USAApproximately 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.http://www.sciencedirect.com/science/article/pii/S2405844023107298CDK4/6 inhibitorHypoxiaImmunogenic cell death |
| spellingShingle | Jung Hyun Lee Justin Daho Lee Kelly Paulson Valentin Voillet Andre Berndt Candice Church Kristina Lachance Song Y. Park Naomi K. Yamamoto Elizabeth A. Cromwell Raphael Gottardo Aude G. Chapuis Paul Nghiem Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma Heliyon CDK4/6 inhibitor Hypoxia Immunogenic cell death |
| title | Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma |
| title_full | Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma |
| title_fullStr | Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma |
| title_full_unstemmed | Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma |
| title_short | Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma |
| title_sort | enhancing immunogenic responses through cdk4 6 and hif2α inhibition in merkel cell carcinoma |
| topic | CDK4/6 inhibitor Hypoxia Immunogenic cell death |
| url | http://www.sciencedirect.com/science/article/pii/S2405844023107298 |
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