Title | Wilms' tumor 1 (WT1) antigen is overexpressed in Kaposi Sarcoma and is regulated by KSHV vFLIP. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Morales AE, Gumenick R, Genovese CM, Jang YYeong, Ouedraogo A, de Garayo MIbáñez, Pannellini T, Patel S, Bott ME, Alvarez J, Mun SSoo, Totonchy J, Gautam A, de la Mora JDelgado, Chang S, Wirth D, Horenstein M, Dao T, Scheinberg DA, Rubinstein PG, Semeere A, Martin J, Godfrey CC, Moser CB, Matining RM, Campbell TB, Borok MZ, Krown SE, Cesarman E |
Journal | PLoS Pathog |
Volume | 20 |
Issue | 1 |
Pagination | e1011881 |
Date Published | 2024 Jan |
ISSN | 1553-7374 |
Keywords | CASP8 and FADD-Like Apoptosis Regulating Protein, Endothelial Cells, Herpesvirus 8, Human, HIV Infections, Humans, Protein Isoforms, Sarcoma, Kaposi, Tumor Microenvironment, WT1 Proteins |
Abstract | In people living with HIV, Kaposi Sarcoma (KS), a vascular neoplasm caused by KS herpesvirus (KSHV/HHV-8), remains one of the most common malignancies worldwide. Individuals living with HIV, receiving otherwise effective antiretroviral therapy, may present with extensive disease requiring chemotherapy. Hence, new therapeutic approaches are needed. The Wilms' tumor 1 (WT1) protein is overexpressed and associated with poor prognosis in several hematologic and solid malignancies and has shown promise as an immunotherapeutic target. We found that WT1 was overexpressed in >90% of a total 333 KS biopsies, as determined by immunohistochemistry and image analysis. Our largest cohort from ACTG, consisting of 294 cases was further analyzed demonstrating higher WT1 expression was associated with more advanced histopathologic subtypes. There was a positive correlation between the proportion of infected cells within KS tissues, assessed by expression of the KSHV-encoded latency-associated nuclear antigen (LANA), and WT1 positivity. Areas with high WT1 expression showed sparse T-cell infiltrates, consistent with an immune evasive tumor microenvironment. We show that major oncogenic isoforms of WT1 are overexpressed in primary KS tissue and observed WT1 upregulation upon de novo infection of endothelial cells with KSHV. KSHV latent viral FLICE-inhibitory protein (vFLIP) upregulated total and major isoforms of WT1, but upregulation was not seen after expression of mutant vFLIP that is unable to bind IKKƴ and induce NFκB. siRNA targeting of WT1 in latent KSHV infection resulted in decreased total cell number and pAKT, BCL2 and LANA protein expression. Finally, we show that ESK-1, a T cell receptor-like monoclonal antibody that recognizes WT1 peptides presented on MHC HLA-A0201, demonstrates increased binding to endothelial cells after KSHV infection or induction of vFLIP expression. We propose that oncogenic isoforms of WT1 are upregulated by KSHV to promote tumorigenesis and immunotherapy directed against WT1 may be an approach for KS treatment. |
DOI | 10.1371/journal.ppat.1011881 |
Alternate Journal | PLoS Pathog |
PubMed ID | 38190392 |
PubMed Central ID | PMC10898863 |
Grant List | R01 CA250074 / CA / NCI NIH HHS / United States UM1 AI068634 / AI / NIAID NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States U01 CA269199 / CA / NCI NIH HHS / United States D43 CA153717 / CA / NCI NIH HHS / United States |
Related Lab:
Related Faculty:
Ethel Cesarman, M.D., Ph.D. Sanjay Patel, M.D., MPH