Pomalidomide restores immune recognition of primary effusion lymphoma through upregulation of ICAM-1 and B7-2

• Published in: PLoS pathogens Vol. 17; no. 1; p. e1009091
• Main Authors: Shrestha, Prabha, Davis, David A., Jaeger, Hannah K., Stream, Alexandra, Aisabor, Ashley I., Yarchoan, Robert
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.01.2021; Public Library of Science (PLoS)
• Subjects: Angiogenesis Inhibitors - pharmacology; Antigens; B-cell lymphoma; B7 antigen; B7-1 antigen; B7-2 Antigen - genetics; B7-2 Antigen - metabolism; Biology and Life Sciences; Biotechnology; Burkitt's lymphoma; CD155 antigen; CD28 antigen; CD58 antigen; CD80 antigen; CD86 antigen; Cell cycle; Cell death; Cell proliferation; Chronic lymphocytic leukemia; Cytokines; Cytotoxicity; Development and progression; Drug therapy; Drugs; Effusion; Enzymes; Epstein-Barr virus; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Genetic regulation; Health aspects; HIV; Host-virus relationships; Human immunodeficiency virus; Humans; Immune system; Infections; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - metabolism; Kaposis sarcoma; Leukemia; LFA-1 antigen; Ligands; Lymphatic leukemia; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma, Primary Effusion - drug therapy; Lymphoma, Primary Effusion - immunology; Lymphoma, Primary Effusion - pathology; Lymphomas; Medicine and Health Sciences; Multiple myeloma; Primary effusion lymphoma; Regulation; Research and Analysis Methods; Sarcoma; Signal Transduction; Surface markers; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Thalidomide - analogs & derivatives; Thalidomide - pharmacology; Tumor cell lines; Tumor Cells, Cultured; Viruses; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1009091

Pomalidomide (Pom) is an immunomodulatory drug that has efficacy against Kaposi’s sarcoma, a tumor caused by Kaposi’s sarcoma-associated herpesvirus (KSHV). Pom also induces direct cytotoxicity in primary effusion lymphoma (PEL), a B-cell malignancy caused by KSHV, in part through downregulation of IRF4, cMyc, and CK1α as a result of its interaction with cereblon, a cellular E3 ubiquitin ligase. Additionally, Pom can reverse KSHV-induced downregulation of MHCI and co-stimulatory immune surface molecules ICAM-1 and B7-2 on PELs. Here, we show for the first time that Pom-induced increases in ICAM-1 and B7-2 on PEL cells lead to an increase in both T-cell activation and NK-mediated cytotoxicity against PEL. The increase in T-cell activation can be prevented by blocking ICAM-1 and/or B7-2 on the PEL cell surface, suggesting that both ICAM-1 and B7-2 are important for T-cell co-stimulation by PELs. To gain mechanistic insights into Pom’s effects on surface markers, we generated Pom-resistant (PomR) PEL cells, which showed about 90% reduction in cereblon protein level and only minimal changes in IRF4 and cMyc upon Pom treatment. Pom no longer upregulated ICAM-1 and B7-2 on the surface of PomR cells, nor did it increase T-cell and NK-cell activation. Cereblon-knockout cells behaved similarly to the pomR cells upon Pom-treatment, suggesting that Pom’s interaction with cereblon is necessary for these effects. Further mechanistic studies revealed PI3K signaling pathway as being important for Pom-induced increases in these molecules. These observations provide a rationale for the study of Pom as therapy in treating PEL and other KSHV-associated tumors.