KSHV: Immune Modulation and Immunotherapy

Abstract

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is associated with KS, primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). To ensure its own survival and propagation, KSHV employs an extensive network of viral proteins to subvert the host immune system, resulting in lifelong latent infection. Modulation of cellular and systemic immune defenses allows KSHV to persist in the host, which may eventually lead to the progression of KSHV-associated cancers. Due to KSHV's reliance on modifying immune responses to efficiently infect its host, immunotherapy is an attractive option for treating KSHV-associated malignancies. In this review, we will focus on the mechanisms by which KSHV evades the immune system and the current immune-related clinical strategies to treat KSHV-associated disease.

Keywords: KSHV; cytokines; immune system modulation; immunotherapy; interferon; oncoviruses.

Figure 1

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) proteins enable evasion of intrinsic immunity. KSHV proteins antagonize viral sensing and interferon responses by targeting a wide variety of host immune factors.

Figure 2

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) proteins enable evasion of cell-mediated immunity, but immunotherapy can restore function. KSHV proteins recruit beneficial helper cell populations, create an inflammatory microenvironment, and interfere with T and NK cell function. Therapies targeting antigen presentation or immune checkpoints provide durable clinical benefit in KSHV-associated malignancies. Anti-PD1 therapy (nivolumab/pembrolizumab) has already demonstrated clinical benefits for KS patients, spurring ongoing clinical trials of anti-PD1 monotherapy and dual anti-PD1/anti-CTLA4 (ipilimumab) therapy. Thalidomide analogs (pomalidomide and lenalidomide) have been shown to increase CD8⁺ T cell killing by modulating PD-L1, MHC-I, and B7 expression, prompting KS clinical trials of monotherapy and dual therapy with liposomal doxorubicin. Thalidomide analogs are being explored in combination with chemotherapy and rituximab for the treatment of PEL in clinical trials. Anti-IL-6 (siltuximab) has shown efficacy for idiopathic multicentric Castleman disease (MCD), prompting clinical trials of anti-IL-6R (tocilizumab) for KSHV-MCD.