The STING agonist, DMXAA, reduces tumor vessels and enhances mesothelioma tumor antigen presentation yet blunts cytotoxic T cell function in a murine model

Abstract

We assessed the murine Stimulator of Interferon Genes (STING) agonist, DMXAA, for anti-mesothelioma potential using the AE17-sOVA model that expresses ovalbumin (OVA) as a neo tumor antigen. Dose response experiments alongside testing different routes of administration identified a safe effective treatment regimen that induced 100% cures in mice with small or large tumors. Three doses of 25mg/kg DMXAA given intra-tumorally every 9 days induced tumor regression and long-term survival (>5 months). Re-challenge experiments showed that tumor-free mice developed protective memory. MTT and propidium-iodide assays showed that DMXAA exerted direct cytotoxic effects at doses >1mg/ml on the murine AE17 and AB1 mesothelioma cell lines. In-vivo studies using a CFSE-based in-vivo proliferation assay showed that DMXAA improved tumor-antigen presentation in tumor-draining lymph nodes, evidenced by OVA-specific OT-1 T cells undergoing more divisions. An in-vivo cytotoxic T lymphocyte (CTL) assay showed that DMXAA blunted the lytic quality of CTLs recognizing the dominant (SIINFEKL) and a subdominant (KVVRFDKL) OVA epitopes. DMXAA reduced tumor vessel size in-vivo and although the proportion of T cells infiltrating tumors reduced, the proportion of tumor-specific T cells increased. These data show careful dosing and treatment protocols reduce mesothelioma cell viability and modulate tumor vessels such that tumor-antigen specific CTLs access the tumor site. However, attempts to enhance DMXAA-induced anti-tumor responses by combination with an agonist anti-CD40 antibody or IL-2 reduced efficacy. These proof-of-concept data suggest that mesothelioma patients could benefit from treatment with a STING agonist, but combination with immunotherapy should be cautiously undertaken.

cGAS-STING pathway mediates activation of dendritic cell sensing of immunogenic tumors

“…Subsequently, DMXAA was identified as an agonist for STING. In murine tumor experiments, DMXAA demonstrated promise, reducing mouse fibrosarcoma size and increasing specific T cell counts [146]. In a phase II clinical trial, a combination therapy of DMXAA with carboplatin (CBP) and paclitaxel exhibited superior efficacy in treating advanced non-small cell lung cancer compared to CBP and paclitaxel alone [147].…”

Targeting cGAS/STING signaling-mediated myeloid immune cell dysfunction in TIME

“…On the other hand, STING agonist DMXXA exerts antitumor effects by decreasing tumor vessel size and increasing the proportion of tumor-specific T cells in the TME [ 237 ]. However, this effect was reduced by anti-CD40 antibodies or IL-2-based immunotherapies.…”

The battle between the innate immune cGAS-STING signaling pathway and human herpesvirus infection

“…The STING agonist 5,6-dimethylfuranone-4-acetic acid (DMXAA) was originally developed by the Auckland Cancer Society Research Centre as an anti-cancer drug and later discovered to be a mouse STING(m-STING) molecular-specific agonist. In vivo studies have shown that DMXAA can reduce the size of tumor blood vessels and increase the levels of tumor antigens ( 108 ). By performing single-cell RNA sequencing, researchers demonstrated that DMXAA could generate a chemokine environment to promote the recruitment of chimeric antigen receptor (CAR) T cells, thereby promoting the transport and persistence of CAR T cells ( 109 ).…”