High-potency synthetic STING agonists rewire myeloid stroma in the tumour microenvironment to amplify immune checkpoint blockade efficacy in refractory pancreatic cancer

• Published in: The Journal of immunology (1950) 2022-05, Vol.208 (1_Supplement), p.163-163.08
• Main Authors: Boda, Akash R, Ager, Casey R, Rajapakshe, Kimal, Lea, Spencer T, Curran, Michael A
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.208.Supp.163.08

Pancreatic ductal adenocarcinoma (PDAC) is clinically unresponsive to immune checkpoint blockade (ICB) immunotherapy. Dense immunosuppressive myeloid stroma (MS) and consequent T cell exclusion from the tumour microenvironment renders PDAC resistant to immune-based therapies. Innate immune activation of the MS via cyclic dinucleotide (CDN) agonists of the STING (Stimulator of Interferon Genes) pathway can trigger T cell infiltration into cold tumours leading to robust anti-tumour immunity. Despite proven therapeutic efficacy in preclinical models, the cellular mechanisms of how CDNs reprogram the suppressive MS to sensitise tumours to ICB is poorly understood. Using multi-omic profiling of MDSCs and M2 Macrophages of human and murine origin, we show that the synthetic STING agonist, IACS-8803, rewires these populations from immunosuppressive to immune-permissive phenotypes in part through inhibition of c-Myc signaling, energy metabolism modulation, and antagonism of cell cycle. Furthermore, dimensionality reduction analyses of multiparameter flow cytometry data and survival studies in a KPC-derived model of PDAC show a proinflammatory remodeling of the MS and an increased T/NK cell infiltration and function by synthetic CDN STING agonists into the tumour that underlies an amplified therapeutic response to ICB. We are the first to report that synthetic CDN STING agonists affect MDSC and M2 macrophage repolarization through altering energy metabolism, cell cycle dynamics and c-Myc signalling. This study uncovers molecular and cellular mechanisms by which high-potency STING agonists drive a proinflammatory conversion of the tumour MS to overcome resistance to ICB in an aggressive orthotopic tumour model of PDAC. Supported by grants from PanCan (206100-90-100300-54-00006617-11111)