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.
Author Info: (1) Biological Engineering, Massachusetts Institute of Technology. (2) Massachusetts Institute of Technology. (3) Biological Engineering, Massachusetts Institute of Technology. (4)
Author Info: (1) Biological Engineering, Massachusetts Institute of Technology. (2) Massachusetts Institute of Technology. (3) Biological Engineering, Massachusetts Institute of Technology. (4) Massachusetts Institute of Technology. (5) KOCH INSTITUTE FOR INTEGRATIVE CANCER RESEARCH, Massachusetts Institute of Technology. (6) Massachusetts Institute of Technology. (7) Massachusetts Institute of Technology. (8) Massachusetts Institute of Technology. (9) Bioengineering, Massachusetts Institute of Technology. (10) Biological Engineering, Massachusetts Institute of Technology djirvine@mit.edu.
