STING Activation Reverses Lymphoma-Mediated Resistance to Antibody Immunotherapy

Abstract

Tumors routinely attract and co-opt macrophages to promote their growth, angiogenesis and metastasis. Macrophages are also the key effector cell for monoclonal antibody (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 Fcγ receptors (FcγR), 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 immunotherapy. Both STINGa and TLRa induced cytokine release, modulated FcγR expression and augmented mAb-mediated tumor cell phagocytosis in vitro. However, only STINGa reversed the suppressive FcγR profile in vivo, providing strong adjuvant effects to anti-CD20 mAb in murine models of lymphoma. Potent adjuvants like STINGa which can improve FcγR activatory:inhibitory (A:I) ratios on TAM are appealing candidates to reprogram TAM and curb tumor-mediated immunosuppression, thereby empowering mAb efficacy.

Differential and sequential immunomodulatory role of neutrophils and Ly6Chiinflammatory monocytes during antiviral antibody therapy

“…Furthermore, our in vitro observations also allowed us to dissect the specific effect of IFN-γ, IFN-I and TNF-α on the enhancement of the functional properties of IC-activated neutrophils and monocytes. Notably, IFN-γ and IFN-I priming (but not TNF-α), led to the upregulation of FcγRs in neutrophils and/or monocytes, in agreement with previous reports in other experimental settings (Dahal et al, 2017; Lehmann et al, 2017; Morquin et al, 2017; Pricop et al, 2001). Consistent with these results, our in vivo work shows that the inflammatory environment resulting from ongoing infection and mAb-treatment also modulates FcγRs expression on neutrophils and monocytes (in particular FcγRIV).…”

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

“…reported to display increased phagocytosis and other markers of macrophage activation; they also recruit new macrophages which serve a phagocytic role in the TME [41][42][43][44] . Consistent with these observations we confirmed that HMDMs transfected with c-di-AMP showed increased phagocytosis and exhibited elongated dendrites compared to mock-transfected populations ( Fig.…”

UC‐1V150, a potent TLR7 agonist capable of activating macrophages and potentiating mAb‐mediated target cell deletion

“…So‐called Danger signals provided by TLR activation enable effective FcγR A:I ratio skewing, but their efficacy in vivo is limited. For instance, the TLR1/2 agonist Pam3CSK4 robustly induced favourable FcγR A:I changes, inflammation and phagocytosis of target cells in vitro, but failed to achieve this in vivo . Therefore, drugs such as UC‐1V150 that promote appropriate FcγR expression profiles in vivo, with the potential for murine to human translation raise the possibility of providing synergistic treatments with existing antibody therapeutics.…”

“…We recently examined the potential of a range of TLR agonists for their ability to activate innate immune cells, including mouse and human macrophages, to improve mAb‐mediated immunotherapy . Although Imiquimod demonstrated some activity, it was unable to significantly augment mAb‐immunotherapy.…”