Using orthotopic murine models of spontaneously metastasizing triple-negative breast cancer, Milling et al. showed that as a neoadjuvant (prior to surgical resection of primary tumors), but not adjuvant (post-surgery) therapy, intratumoral injection of STING agonists combined with systemic injection of longer-lived IL-2 and anti-PD-1 arrested tumor growth, extended host survival, and induced antitumor T cell responses. Prevention of metastatic relapse required lung-infiltrating NK cells expressing granzyme B, IFNγ, TNFα, perforin, NKG2D, PD-1, and receptors for IL-2 and STING-induced type I IFNs, thus potentiating therapeutic effects.
Contributed by Paula Hochman
ABSTRACT: Combination immunotherapy treatments that recruit both innate and adaptive immunity have the potential to increase 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 interleukin-2 (IL2) and anti-PD-1 checkpoint blockade (hereafter CIP therapy) to drive innate and adaptive anti-tumor 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 anti-tumor 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 interferons (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.