Direct activation of
tumor infiltrating antigen-presenting cells (APCs) by intratumoral injection of
STING agonists (STINGa) leads to regression of the treated
lymphoma tumor. Because
STING activation induces apoptosis in
lymphoma cells in vitro, we distinguished between the direct therapeutic vs the indirect immunotherapeutic properties of STINGa in vivo. Employing wild-type or
STING knockout hosts bearing either wild-type or
STING knockout
tumor cells, we demonstrated that local
tumor regression is totally dependent on
STING expression by the host and is therefore immune mediated. However, distant untreated
tumors are weakly affected after injection of STINGa to a single
tumor site. Therefore, using the STINGa currently being tested in clinical trials, we screened for
immunomodulatory agents that could synergize with the
STING pathway to induce a systemic antitumor immune response and regression of distant
tumors. We combined the STINGa with agents that improve APC or T-cell function. We found that modulation of both APCs and T cells can enhance control of distant
lymphoma tumors by STINGa. In particular, adding an anti-GITR antibody induced lymphocyte expansion in the lymph node draining the treated site followed by increased T-cell infiltration in the distant
tumor. Furthermore, more of these CD8 T cells at the distant site expressed PD-1. Therefore, blockade of PD-1 further enhanced
tumor control at the distant site, leading to cure in 50% of the mice. These preclinical data provide the rationale for testing local injection of STINGa followed by agonistic anti-GITR and anti-PD-1
antibodies as
immunotherapy for human
lymphoma.