Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma
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
Affiliations
Jung Hyun Lee
Department 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.
Justin Daho Lee
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
Kelly Paulson
Department 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, USA
Valentin Voillet
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Andre Berndt
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
Candice Church
Department of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA
Kristina Lachance
Department of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA
Song Y. Park
Department of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA
Naomi K. Yamamoto
Medical Scientist Training Program, University of Washington, Seattle, WA, USA
Elizabeth A. Cromwell
Seattle Cancer Care Alliance, Seattle, WA, USA
Raphael Gottardo
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Aude G. Chapuis
Department 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, USA
Paul Nghiem
Department 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, USA
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.
