A Viral-Encoded Homologue of IPS-1 Modulates Innate Immune Signaling During KSHV Lytic Replication.

Modulation of innate immunity is critical for virus persistence in a host. In particular, viral-encoded disruption of type I interferon, a major antiviral cytokine induced to fight viral infection, is a key component in the repertoire of viral pathogenicity genes. We have identified a previously undescribed open reading frame within the Kaposi's sarcoma-associated herpesvirus (KSHV) genome that encodes a homologue of the human IPS-1 (also referred to as MAVS) protein that we have termed viral-IPS-1 (v-IPS-1). This protein is expressed during the lytic replication program of KSHV, and expression of v-IPS-1 blocks induction of type I interferon upstream of the TRAF3 signaling node including signaling initiated via both the RLR and TLR3/4 signaling axes. This disruption of signaling coincides with destabilization of the cellular innate signaling adaptors IPS-1 and TRIF along with a concatenate stabilization of the TRAF3 protein. Additionally, expression of v-IPS-1 leads to decreased antiviral responses indicating a blot to type I interferon induction during viral infection. Taken together, v-IPS-1 is the first described viral homologue of IPS-1 and this viral protein leads to reprogramming of innate immunity through modulation of type I interferon signaling during KSHV lytic replication.

Targeting STAT3 in tumor-associated antigen-presenting cells as a strategy for kidney and bladder cancer immunotherapy.

Introduction: Immune checkpoint blockade (ICB) improved clinical outcomes in renal and bladder cancer patients, but the response rates remain limited especially in metastatic disease. While STAT3 transcription factor is well-known master regulator of tumor immune evasion, little is known about the role of STAT3 in the resistance of renal or bladder cancers to immunotherapy. Methods: To better understand immune alterations associated with ICB resistance, we assessed blood biomarkers in renal cancer patients classified as responders or non-responders to first line nivolumab/ipilimumab immunotherapy. Results: We observed that non-responders showed elevated levels of proinflammatory mediators, such as IL-1RA, IL-6, IL-8 and to lesser extent IL-10, which are associated with STAT3 activation and tumor immunosuppression. In addition, we found STAT3 activation primarily in circulating myeloid immune cells such as tolerogenic MDSCs. To assess whether STAT3 inhibition within these cell subsets can promote antitumor immune responses and/or enhance sensitivity to ICB in vivo, we used an original antisense oligonucleotide (ASO) strategy for myeloid-cell selective STAT3 knockdown (CpG-STAT3ASO). Our results in syngeneic models of renal and bladder cancers in mice demonstrated potent antitumor activity of CpG-STAT3ASO alone in contrast to PD1 blockade alone in both models. The CpG-STAT3ASO/anti-PD1 combination improved therapeutic efficacy especially against bladder tumors. Therapeutic efficacy correlated with activation of dendritic cells (DCs) and M1 macrophages in the tumor microenvironment, reduced percentages of regulatory T cells (Tregs) and the expansion of CD8 T cells in both tumor models. Discussion/Conclusion: Our study underscores the potential of using myeloid-cell targeted CpG-STAT3 inhibitors for genitourinary cancer therapy to disrupt tolerogenic signaling, restore immune cell activity and sensitivity to immune checkpoint inhibitors and/or T cell-based immunotherapies.