STING and TLR 7/8 Agonist combination can improve immune checkpoint blockade therapy efficiency.

Abstract Despite significant advancements in immune checkpoint blockade (ICB) therapy, only few patients respond to the treatment. Non-immunogenic cold tumors lack T-cell infiltration, which results in reduced ICB therapeutic efficiency. Immune adjuvants can reprogram the non-immunogenic cold tumor microenvironment (TME) to inflamed hot TME by activating antigen presenting cells and improving T-cell homing. Here, we investigate the potentials of 558 (a novel TLR 7/8 agonist) and ADU-S100 (stimulator of interferon gene (STING) agonist in clinical trials) combination on improving the activity of ICB. Human TLR-specific reporter cell assay using HEK-Blue™-hTLR7 and 8, confirmed the activation of both TLR 7 and TLR 8 with EC50 of 0.18 µM and 5.34 µM respectively, when treated with 558. In addition, treatment of human PBMCs with 558 increased the IFN-γ and TNF-α cytokine secretions. Moreover, the levels of IL-10, an anti-inflammatory cytokine were not increased upon treatment with 558. Although treatment of bone marrow derived dendritic cells (BMDC) with 558 resulted in CD40 expression, a reduced expression of CD80 and CD86, costimulatory molecules that are required for T-cell activation, was observed. Interestingly, 558 in combination with ADU-S100 not only increased the CD40 expression but also improved the expression of CD80 (4-fold) and CD86 on BMDCs. Furthermore, the levels of pro-inflammatory cytokines TNF-α and IL-6 was significantly increased when BMDCs were treated with 558 and ADU-S100 combination compared to the individual treatments. TME constitute M2 polarized macrophages that promote secretion of anti-inflammatory cytokines and favor tumor progression. Interestingly, 558 and ADU-S100 combination reduced the expression of CD206, a mannose receptor that is highly expressed on M2 macrophages and improved the expression of CD80 (25-fold) and CD86 (6-fold) compared to 558 treatments alone. These results confirmed the polarization of M2 macrophages to immunogenic M1 macrophages. Overall, these studies indicate promising potential of 558 and ADU-S100 combination in reprogramming the TME to aid in effective cancer treatments. Citation Format: Vishnu Revuri, Shubhmita Bhatnagar, John Schultz, Peter Larson, David M. Ferguson, Jayanth Panyam. STING and TLR 7/8 Agonist combination can improve immune checkpoint blockade therapy efficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5587.