Merkel cell carcinoma and immune evasion: Merkel cell polyomavirus small T-antigen induced surface changes can be reverted by therapeutic intervention
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Merkel cell carcinoma and immune evasion: Merkel cell polyomavirus small T-antigen induced surface changes can be reverted by therapeutic intervention. / Schlemeyer, Tabea; Ohnezeit, Denise; Virdi, Sanamjeet; Körner, Christian; Weißelberg, Samira; Starzonek, Sarah; Schumacher, Udo; Grundhoff, Adam; Indenbirken, Daniela; Albertini, Silvia; Fischer, Nicole.
In: J INVEST DERMATOL, Vol. 142, No. 11, 11.2022, p. 3071-3081.e13.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Merkel cell carcinoma and immune evasion: Merkel cell polyomavirus small T-antigen induced surface changes can be reverted by therapeutic intervention
AU - Schlemeyer, Tabea
AU - Ohnezeit, Denise
AU - Virdi, Sanamjeet
AU - Körner, Christian
AU - Weißelberg, Samira
AU - Starzonek, Sarah
AU - Schumacher, Udo
AU - Grundhoff, Adam
AU - Indenbirken, Daniela
AU - Albertini, Silvia
AU - Fischer, Nicole
N1 - Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2022/11
Y1 - 2022/11
N2 - Merkel cell polyomavirus is the causative agent for most Merkel cell carcinomas (MCCs). This highly aggressive skin cancer shows rapid progression, with metastasis being a significant challenge for patient therapy. Virus-positive MCCs show low mutation rates, and tumor cell proliferation is dependent on viral oncoproteins small T antigen (sT) and large T antigen. Although the role of sT and large T antigen in early events of tumorigenesis has been extensively studied, their role in tumor progression has been scarcely addressed. In this study, we investigate the possible mechanisms of how Merkel cell polyomavirus oncoproteins, particularly sTs, contribute to metastasis. We show that sT specifically affects selectin ligand binding and processing by altering the presentation of multiple MCC surface molecules, thereby influencing initial metastasis events and tumor cell immune recognition. Furthermore, we show that sT regulates the surface antigen CD47, which inhibits phagocytosis by macrophages. By applying either sT short hairpin RNAs, CD47-targeted small interfering RNAs, or a therapeutic anti-CD47 antibody, we show that immune recognition of MCC cells can be restored. Thus, CD47 is a promising therapeutic target on MCC cells. Blocking the CD47‒SIRPα interaction effectively promotes phagocytosis of MCC cells and might be a promising combinatorial immunotherapy approach together with PD-1/PD-L1 axis in MCC treatment.
AB - Merkel cell polyomavirus is the causative agent for most Merkel cell carcinomas (MCCs). This highly aggressive skin cancer shows rapid progression, with metastasis being a significant challenge for patient therapy. Virus-positive MCCs show low mutation rates, and tumor cell proliferation is dependent on viral oncoproteins small T antigen (sT) and large T antigen. Although the role of sT and large T antigen in early events of tumorigenesis has been extensively studied, their role in tumor progression has been scarcely addressed. In this study, we investigate the possible mechanisms of how Merkel cell polyomavirus oncoproteins, particularly sTs, contribute to metastasis. We show that sT specifically affects selectin ligand binding and processing by altering the presentation of multiple MCC surface molecules, thereby influencing initial metastasis events and tumor cell immune recognition. Furthermore, we show that sT regulates the surface antigen CD47, which inhibits phagocytosis by macrophages. By applying either sT short hairpin RNAs, CD47-targeted small interfering RNAs, or a therapeutic anti-CD47 antibody, we show that immune recognition of MCC cells can be restored. Thus, CD47 is a promising therapeutic target on MCC cells. Blocking the CD47‒SIRPα interaction effectively promotes phagocytosis of MCC cells and might be a promising combinatorial immunotherapy approach together with PD-1/PD-L1 axis in MCC treatment.
U2 - 10.1016/j.jid.2022.04.029
DO - 10.1016/j.jid.2022.04.029
M3 - SCORING: Journal article
C2 - 35636504
VL - 142
SP - 3071-3081.e13
JO - J INVEST DERMATOL
JF - J INVEST DERMATOL
SN - 0022-202X
IS - 11
ER -