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STING activation reverses lymphoma-mediated resistance to antibody immunotherapy

May 31, 2017

In the context of immunotherapy, the pro- or anti-tumor activity of macrophages is a matter of nurture over nature. Macrophages in a healthy environment play a key role in inducing an adaptive immune response and clearing cellular debris; however, tumors create an immunosuppressive microenvironment that imprints a pro-tumor signature on macrophages, including a low ratio of activating to inhibitory (A:I) Fcɣ receptors (FcɣR). In this study, Dahal et al. show that tipping the balance towards a higher A:I ratio of FcɣRs can restore the pro-inflammatory, anti-tumor immune function of tumor-associated macrophages (TAMs) and improve the efficacy of monoclonal antibody (mAb) therapies.

Researchers tested a variety of toll-like receptor (TLR) and stimulator of interferon gene (STING) agonists in search of specific ligands capable of modifying FcɣR expression, increasing the A:I ratio, and augmenting the ability of TAMs to phagocytose antibody-opsonized tumor cells. The human and mouse STING agonists, and the TLR3 agonist Poly I:C (among all the TLR agonists) strongly increased the expression of activating FcɣRs without affecting the expression of inhibitory FcɣRs on murine macrophages, thereby increasing their phagocytic activity. In experiments with human macrophages, however, only the STING agonists, but not Poly I:C, were able to increase the A:I ratio, the expression of the activation markers CD40 and CD38, the production of type I interferons, and the phagocytic activity.

Having established their potential in vitro, researchers moved to explore how TLR and STING agonists affect FcɣR expression and antibody dependent cellular phagocytosis in an in vivo tumor model. Treatment with an anti-human CD20 antibody alone cleared about 40% of adoptively-transferred target B cells that transgenically expressed human CD20 in mice, while priming mice with TLR3 agonist led to a 60% depletion of target cells, and priming mice with the murine STING ligand DMXAA showed about a 90% depletion of target cells.

In a more challenging, immunosuppressive murine B cell lymphoma, the researchers ran experiments in which they allowed the tumor to run its course for one week before applying the TLR3 and STING agonists, and anti-CD20 to see whether any of the therapeutic combinations could reverse the anti-CD20 resistance of the tumor. The TLR3 agonist failed to recover the preferred FcɣR profile; however, DMXAA remained effective as an adjuvant, reversed the tumor-induced effect on the A:I ratio, and increased the phagocytic activity of TAMs. Further, compared to the very modest survival effects of either treatment alone, over 90% mice primed with DMXAA before anti-CD20 mAb therapy were cured. This effect was dependent on FcɣR modulation or type I interferon, but not on the induction of a CD8+ T cell response. Based on the results, the researchers concluded that STING agonists have the potential to augment the efficacy of mAb therapy by enhancing the phagocytosis of antibody opsonized tumor cells.

by Lauren Hitchings

References:

Dahal, L.N., Dou, L., Hussain, K., Liu, R., Earley, A., Cox, K.L., Murinello, S., Tracy, I., Forconi, F., Steele, A.J., Duriez, P., Gomez-Nicola, D., Teeling, J.L., Glennie, M.J., Cragg, M.S. and Beers, S.A. STING activation reverses lymphoma-mediated resistance to antibody immunotherapy. Cancer Res. 2017 May 16.

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