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

Abstract

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.

Daratumumab induces cell-mediated cytotoxicity of primary effusion lymphoma and is active against refractory disease

“…Pomalidomide (Pom), an immunomodulatory drug approved for use with Dara in relapsed MM, has been shown by our group to increase expression of certain immune surface markers in several virus-induced tumor lines. 23 , 37 , 38 Pom also inhibits the growth of PEL lines in vitro 37 , 39 ( Figure 7a ). We assessed whether Pom could enhance Dara’s activity against PEL cells by raising CD38 expression.…”

Today's Kaposi sarcoma is not the same as it was 40 years ago, or is it?

“…Their primary target is Cereblon, which is an essential gene in PEL 195 . In addition to its cell intrinsic role in survival, pomalidomide modulates the immune response at both a cellular and systemic level 196 . Pomalidomide restores B7‐2, ICAM‐1, and MHC1 levels in latent and lytic PEL cells 197 .…”

Reshaping the tumor microenvironment: The versatility of immunomodulatory drugs in B-cell neoplasms

“…Pomalidomide has been approved for the treatment of MM, which is more powerful than lenalidomide and shows efficacy in cases that are resistant to lenalidomide ( 30 , 31 ). Furthermore, it is now under extensive exploration in preclinical or clinical studies on aggressive BCLs including DLBCL, primary effusion lymphoma (PEL) and primary central nervous system lymphoma (PCNSL) ( 32 – 37 ). Avadomide (also called CC-122) ( Figure 1A ), a novel modulator of cereblon E3 ubiquitin ligase (CELMoD) exhibiting potent anti-lymphoma and immunomodulatory activities, is currently in phase I trials ( 38 , 39 ).…”