Neoadjuvant STING Activation, Extended Half-life IL2, and Checkpoint Blockade Promote Metastasis Clearance via Sustained NK-cell Activation

• Published in: Cancer immunology research 2022-01, Vol.10 (1), p.26-39
• Main Authors: Milling, Lauren E, Garafola, Daniel, Agarwal, Yash, Wu, Shengwei, Thomas, Ayush, Donahue, Nathan, Adams, Josetta, Thai, Nikki, Suh, Heikyung, Irvine, Darrell J
• Format: Article
• Language: English
• Subjects: Animals; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Breast Neoplasms - secondary; Cell Line, Tumor; Half-Life; Immune Checkpoint Inhibitors - pharmacology; Immunotherapy; Interferon Type I - metabolism; Interleukin-2 - pharmacology; Interleukin-2 Receptor alpha Subunit - metabolism; Killer Cells, Natural - immunology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Neoadjuvant Therapy; Neoplasm Metastasis
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-21-0247

Combination immunotherapy treatments that recruit both innate and adaptive immunity have the potential to increase cancer response rates by engaging a more complete repertoire of effector mechanisms. Here, we combined intratumoral STimulator of INterferon Genes (STING) agonist therapy with systemically injected extended half-life IL2 and anti-PD-1 checkpoint blockade (hereafter CIP therapy) to drive innate and adaptive antitumor immunity in models of triple-negative breast cancer. Unlike treatment with the individual components, this trivalent immunotherapy halted primary tumor progression and led to long-term remission for a majority of animals in two spontaneously metastasizing orthotopic breast tumor models, though only as a neoadjuvant therapy but not adjuvant therapy. CIP therapy induced antitumor T-cell responses, but protection from metastatic relapse depended on natural killer (NK) cells. The combination of STING agonists with IL2/anti-PD-1 synergized to stimulate sustained granzyme and cytokine expression by lung-infiltrating NK cells. Type I IFNs generated as a result of STING agonism, combined with IL2, acted in a positive-feedback loop by enhancing the expression of IFNAR-1 and CD25 on lung NK cells. These results suggest that NK cells can be therapeutically targeted to effectively eliminate tumor metastases. .