KSHV infection skews macrophage polarisation towards M2-like/TAM and activates Ire1 α-XBP1 axis up-regulating pro-tumorigenic cytokine release and PD-L1 expression

Abstract

Background Kaposi’s Sarcoma Herpesvirus (KSHV) is a gammaherpesvirus strongly linked to human cancer. The virus is also able to induce immune suppression, effect that contributes to onset/progression of the viral-associated malignancies. As KSHV may infect macrophages and these cells abundantly infiltrate Kaposi’s sarcoma lesions, in this study we investigated whether KSHV-infection could affect macrophage polarisation to promote tumorigenesis. Methods FACS analysis was used to detect macrophage markers and PD-L1 expression. KSHV infection and the molecular pathways activated were investigated by western blot analysis and by qRT-PCR while cytokine release was assessed by Multi-analyte Kit. Results We found that KSHV infection reduced macrophage survival and skewed their polarisation towards M2 like/TAM cells, based on the expression of CD163, on the activation of STAT3 and STAT6 pathways and the release of pro-tumorigenic cytokines such as IL-10, VEGF, IL-6 and IL-8. We also found that KSHV triggered Ire1 α-XBP1 axis activation in infected macrophages to increase the release of pro-tumorigenic cytokines and to up-regulate PD-L1 surface expression. Conclusions The findings that KSHV infection of macrophages skews their polarisation towards M2/TAM and that activate Ire1 α-XBP1 to increase the release of pro-tumorigenic cytokines and the expression of PD-L1, suggest that manipulation of UPR could be exploited to prevent or improve the treatment of KSHV-associated malignancies.

ER Stress, UPR Activation and the Inflammatory Response to Viral Infection

“…Although the role of UPR activation in the release of proinflammatory, antiviral, and anti-inflammatory cytokines during viral infection is still under investigation, there are several studies showing that it contributes to inflammation [ 21 , 33 ]. The example of some viruses being able to activate UPR or one of its arms to enhance cytokine production is reported in Table 1 .…”

“…Regarding herpesviruses, the majority of which are ubiquitous viruses, they are known to infect and persist in several cell types, and the chronic infection that they cause may induce long lasting or chronic inflammation in several tissues. This facilitates the onset of a variety of inflammation-based diseases ranging from gastritis, inflammatory bowel diseases, autoimmune diseases, neurodegenerative diseases, and cancer [ 33 , 37 , 38 , 39 ]. Other completely different viruses such as hepatitis viruses may also cause diseases, to whose pathogenesis the inflammatory response strongly contributes.…”

IRE1 Alpha/XBP1 Axis Sustains Primary Effusion Lymphoma Cell Survival by Promoting Cytokine Release and STAT3 Activation

“…Accordingly, here, we found that in addition to impairing cytokine production, Ire1alpha/XBP1 axis inhibition led to a reduction in STAT3 phosphorylation in these cells. The close relationship between IRE1alpha/XBP1 axis activation and pro-inflammatory/immune suppressive cytokine secretion has been recently shown by our laboratory in macrophages infected by KSHV [ 27 ], the same virus carried by PEL cells and involved in the etiology of this lymphoma. Moreover, IL-6, IL-10 and VEGF, produced by cancer cells, may activate STAT3 in a paracrine fashion in the cells present in the tumor microenvironment, such as myeloid cells or fibroblasts, transforming them into cells that support tumor growth [ 28 ].…”

Human Herpesvirus and the Immune Checkpoint PD-1/PD-L1 Pathway: Disorders and Strategies for Survival

“…Strong expression of PD-1 and PD-L1 were reported in KS specimens from AIDS patients [57]. In addition to cancers, KSHV can infect monocytes and macrophages and was shown to induce expression of PD-L1 [58,59]. Interestingly, lytic KSHV infection has been shown to increase PD-L1 expression [57,59].…”