Overcoming resistance to STING agonist therapy to incite durable protective antitumor immunity

Abstract

BackgroundActivating the Stimulator of Interferon Genes (STING) adaptor incites antitumor immunity against immunogenic tumors in mice, prompting clinical trials to test STING activators. However, STING signaling in the tumor microenvironment (TME) during development of Lewis lung carcinoma (LLC) suppresses antitumor immunity to promote tumor growth. We hypothesized that local immune balance favoring suppression of antitumor immunity also attenuates antitumor responses following STING activation. The purpose of this study was to evaluate how STING activation impacts antitumor responses in mice bearing LLC tumors.MethodsMice bearing established LLC tumors were treated with synthetic cyclic diadenyl monophosphate (CDA) to activate STING. Mice were monitored to assess LLC tumor growth, survival and protective antitumor immunity. Transcriptional and metabolic analyses were used to identify pathways responsive to CDA, and mice were co-treated with CDA and drugs that disrupt these pathways.ResultsCDA slowed LLC tumor growth but most CDA-treated mice (77%) succumbed to tumor growth. No evidence of tumor relapse was found in surviving CDA-treated mice at experimental end points but mice were not immune to LLC challenge. CDA induced rapid increase in immune regulatory pathways involving programmed death-1 (PD-1), indoleamine 2,3 dioxygenase (IDO) and cyclooxygenase-2 (COX2) in the TME. PD-1 blockade enhanced antitumor responses to CDA and increased mouse survival but mice did not eliminate primary tumor burdens. Two IDO inhibitor drugs had little or no beneficial effects on antitumor responses to CDA. A third IDO inhibitor drug synergized with CDA to enhance tumor control and survival but mice did not eliminate primary tumor burdens. In contrast, co-treatments with CDA and the COX2-selective inhibitor celecoxib controlled tumor growth, leading to uniform survival without relapse, and mice acquired resistance to LLC re-challenge and growth of distal tumors not exposed directly to CDA. Thus, mice co-treated with CDA and celecoxib acquired stable and systemic antitumor immunity.ConclusionsSTING activation incites potent antitumor responses and boosts local immune regulation to attenuate antitumor responses. Blocking STING-responsive regulatory pathways synergizes with CDA to enhance antitumor responses, particularly COX2 inhibition. Thus, therapy-induced resistance to STING may necessitate co-treatments to disrupt regulatory pathways responsive to STING in patients with cancer.

STING agonist-based treatment promotes vascular normalization and tertiary lymphoid structure formation in the therapeutic melanoma microenvironment

“…Notably, we observed that PD-L1, Ptgs2/COX2, Ptges and Arg2 expression were strongly upregulated on STING-activated DCs, suggesting these APCs may not mediate optimal/sustained immunostimulatory activity in vivo (online supplemental figure S6). 63 Other preclinical studies have indeed demonstrated therapeutic synergy when combining STING agonists with checkpoint inhibitors [44][45][46] or COX-2 inhibitors 15 in vivo, suggesting that antagonism of immunoregulatory pathways induced by STING activation might prove crucial for successful treatment of multifocal, advanced-stage disease. We are currently investigating the therapeutic impact of combined treatment with STING agonists+anti-PD-L1 and/or inhibitors of PTGES, PTGS2/ COX-2 and ARG2 to determine impact on VN, TLS formation, TIL repertoire and tumor growth in our murine melanoma models.…”

“…in transplantable s.c. murine B16.F10 melanoma models. In order to avoid vasoablation and T cell apoptosis observed with high, near-MTD doses of STING agonists, [14][15][16] and based on preliminary findings for tumor ulceration necessitating euthanasia at doses >5 µg/tumor (data not shown), we adopted the use of a low dose (5 µg/tumor; ie, ~100-fold lower than conventional dosing) of ADU S-100 for i.t. injections administered on days 10, 14 and 17 posttumor inoculation (figure 1A).…”

The Complexity of the cGAS-STING Pathway in CNS Pathologies

“…Moreover, the double-edge sword of the immune system in suppressing and promoting tumour growth poses a challenge in targeting STING as a cancer therapy. Prolonged activation of STING can result in a tolerogenic immune response, chronic neuroinflammation, increased tumour growth and impaired T-lymphocyte function all of which are detrimental in cancer treatment ( Huang et al, 2013 ; Ahn et al, 2014 ; Larkin et al, 2017 ; Lemos et al, 2020 ). Conversely, prolonged suppression of the neuroinflammatory response by STING inhibition may be detrimental in the treatment of diseases that require an acute, beneficial initial neuroinflammatory response as seen in spinal cord injury, stroke, and traumatic brain injury ( DiSabato et al, 2016 ; Simon et al, 2017 ; Shields et al, 2020 ).…”

STINGing the Tumor Microenvironment to Promote Therapeutic Tertiary Lymphoid Structure Development

“…Given the ability of STING agonists to promote robust proinflammatory responses in tumor-associated stromal cells, it is perhaps not surprising that these agents are competent to initiate the development of non-classical, immature TLS within the TME (67). And even though treatment of tumor-bearing mice with STING agonists leads to reduced levels of tumor-associated myeloid-derived suppressor cells (MDSC) and Treg cells (107,108), these regimens promote compensatory activation of immune regulatory pathways by augmenting expression of arginase-2 (ARG2), cyclooxygenase-2 (COX2/PTGS2), indoleamine 2,3 dioxygenase (IDO), programmed death-1 (PD-1), programmed death ligand-1 (PD-L1) and prostaglandin E synthase (PTGES) within the TME (67,(109)(110)(111). Hence, combined treatment protocols that include STING agonists and antagonists of these regulatory pathways would be anticipated to enhance/sustain inflammation within the TME in support of TLS formation/maintenance and improved host control of tumor growth.…”

“…Hence, combined treatment protocols that include STING agonists and antagonists of these regulatory pathways would be anticipated to enhance/sustain inflammation within the TME in support of TLS formation/maintenance and improved host control of tumor growth. While the formation of TLS has yet to be investigated as a therapeutic endpoint in translational models of such combination treatment protocols, therapeutic synergy has been observed for regimens combining STING agonists with inhibitors of COX2 (Celecoxib) or IDO (BMS-986205), or antagonist anti-PD1 and/or anti-PD-L1 antibodies ( 107 , 109 , 112 ).…”