STING Activation Reverses Lymphoma-Mediated Resistance to Antibody Immunotherapy

Tumors routinely attract and co-opt macrophages to promote their growth, angiogenesis, and metastasis. Macrophages are also the key effector cell for mAb therapies. Here we report that the tumor microenvironment creates an immunosuppressive signature on tumor-associated macrophages (TAM), which favors expression of inhibitory rather than activating Fc gamma receptors (Fc gamma R), thereby limiting the efficacy of mAb immunotherapy. We assessed a panel of TLR and STING agonists (a) for their ability to reprogram macrophages to a state optimal for mAb immuno-therapy. Both STINGa and TLRa induced cytokine release, modulated Fc gamma R expression, and augmented mAb-mediated tumor cell phagocytosis in vitro. However, only STINGa reversed the suppressive FcgR profile in vivo, providing strong adjuvant effects to anti-CD20 mAb in murine models of lymphoma. Potent adjuvants like STINGa, which can improve FcgR activatory: inhibitory (A: I) ratios on TAM, are appealing candidates to reprogram TAM and curb tumor-mediated immunosuppression, thereby empowering mAb efficacy.