Oncotarget

Priority Research Papers:

Restoration of immune surface molecules in Kaposi sarcoma-associated herpes virus infected cells by lenalidomide and pomalidomide

David A. Davis _, Suraj Mishra, Holda A. Anagho, Ashley I. Aisabor, Prabha Shrestha, Victoria Wang, Yuki Takamatsu, Kenji Maeda, Hiroaki Mitsuya, Jerome B. Zeldis and Robert Yarchoan

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Oncotarget. 2017; 8:50342-50358. https://doi.org/10.18632/oncotarget.17960

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Abstract

David A. Davis1,*, Suraj Mishra1,*, Holda A. Anagho1, Ashley I. Aisabor1, Prabha Shrestha1, Victoria Wang1, Yuki Takamatsu1, Kenji Maeda1, Hiroaki Mitsuya1, Jerome B. Zeldis2 and Robert Yarchoan1

1 HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

2 Celgene Corp., Summit, NJ, USA

* These authors have contributed equally to this study

Correspondence to:

David A. Davis, email:

Keywords: Kaposi sarcoma-associated herpesvirus, pomalidomide, lenalidomide, major histocompatibility class I, ICAM-1

Received: April 25, 2017 Accepted: April 28, 2017 Published: May 17, 2017

Abstract

Kaposi sarcoma-associated herpesvirus (KSHV) is the cause of several tumors, including Kaposi sarcoma and primary effusion lymphoma (PEL). Most viruses have evolved means of escaping immune recognition. KSHV downregulates MHC-I expression during lytic infection, and expression of ICAM-1 and B7-2 (CD86) during latent infection, allowing evasion of T cell and natural killer immunity respectively. These effects are largely mediated by two KSHV-encoded proteins, K3 and K5. We show here that lenalidomide (Len) and pomalidomide (Pom) prevent down-regulation of MHC-I during lytic activation, and restore ICAM-1 and B7-2 surface expression in latently infected PEL cells. Importantly, these changes occurred at clinically achievable concentrations and prior to any cytotoxic effects. Exploration of the mechanism revealed that Pom blocked lytic down-regulation of MHC-I induced by transfection with K3 but not K5. Although Pom alone did not significantly increase HLA mRNA expression in PEL cells, it did blunt the butyrate-induced decrease in MHC-I mRNA expression and decreased the upregulation of K3 mRNA in lytic cells. Virus-induced tumors express foreign antigens, but immunotherapy can be thwarted by viral strategies to evade immune recognition. The effects of Pom and Len described here can prevent these strategies and support the use of these drugs to treat KSHV-induced tumors.


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