Introduction: Soft tissue sarcomas STS are highly metastatic, connective-tissue lineage solid cancers. Immunologically, sarcomas are frequently characterized by a paucity of tumor infiltrating lymphocytes and an immune suppressive microenvironment. Activation of the STING pathway can induce potent immune-driven anti-tumor responses within immunogenic solid tumors; however, this strategy has not been evaluated in immunologically cold sarcomas.
Herein, we assessed the therapeutic response of intratumoral STING activation in an immunologically cold murine model of undifferentiated pleomorphic sarcoma UPS. Surviving mice all rejected UPS re-challenge in the hindlimb and lung. Therapeutic efficacy of STING was inhibited by lymphocyte deficiency but unaffected by macrophage deficiency. Immune phenotyping demonstrated enrichment of lymphocytic responses in tumors at multiple timepoints following treatment.
Discussion: These data suggest intratumoral activation of the STING pathway elicits local and systemic anti-tumor immune responses in a lymphocyte poor sarcoma model and deserves further evaluation as an adjunctive local and systemic treatment for sarcomas.
Soft tissue sarcomas STS are rare malignancies derived from mesenchymal lineage tissues such as muscle, adipose, fibrous tissue, vessels, and skin 1. There are over 50 unique histologic subtypes of STS 1 , with undifferentiated pleomorphic sarcoma UPS being the most common subtype in adults 4.
Unresectable metastatic disease is rapidly fatal 1 , 6 β 8 and there is a pressing need for new systemic therapies for STS patients 9. Immunotherapies are revolutionizing cancer care 10 β 13 , yet unfortunately, sarcoma remains recalcitrant to multiple clinically approved immune-based therapies 14 β Relative to other solid cancers, most sarcomas are deficient in tumor infiltrating lymphocytes TILs 19 β 21 , which, like other solid cancers, predicts poor therapeutic responses to immune checkpoint inhibition ICI The stimulator of interferon genes STING receptor is a highly conserved intracellular protein involved in the dsDNA sensing apparatus of eukaryotic cells and is responsible for Type I IFN and cytokine production in response to cytosolic DNA derived from pathogens and corrupt host cells 26 , The STING pathway provides a critical link between the innate and adaptive compartments of the immune system and is a vital component of cancer immunity 19 , 21 , In pre-clinical models of classically inflamed solid tumors, intratumoral i.
