STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation

Abstract

Cytosolic DNA sensing is an important process during the innate immune response that activates the Stimulator of Interferon Genes (STING) adaptor and induce interferon type I (IFN-I). STING incites spontaneous immunity during immunogenic tumor growth and accordingly, STING agonists induce regression of therapy-resistant tumors. However DNA, STING agonists and apoptotic cells can also promote tolerogenic responses via STING by activating immunoregulatory mechanisms such as indoleamine 2,3 dioxygenase (IDO). Here, we show that IDO activity induced by STING activity in the tumor microenvironment (TME) promoted the growth of Lewis lung carcinoma (LLC). While STING also induced IDO in tumor-draining lymph nodes (TDLNs) during EL4 thymoma growth, this event was insufficient to promote tumorigenesis. In the LLC model, STING ablation enhanced CD8+ T cell infiltration and tumor cell killing while decreasing myeloid-derived suppressor cell infiltration and IL-10 production in the TME. Depletion of CD8+ T cells also eliminated the growth disadvantage of LLC tumors in STING-deficient mice, indicating that STING signaling attenuated CD8+ T cell effector functions during tumorigenesis. In contrast to native LLC tumors, STING signaling did not promote growth of neoantigen-expressing LLC, nor did it induce IDO in TDLN. Similarly, STING failed to promote growth of B16 melanoma or to induce IDO activity in TDLN in this setting. Thus, our results show how STING-dependent DNA sensing can enhance tolerogenic states in tumors characterized by low antigenicity, and how IDO inhibition can overcome this state by attenuating tumor tolerance. Further, our results reveal a greater complexity in the role of STING signaling in cancer, underscoring how innate immune pathways in the TME modify tumorigenesis in distinct tumor settings, with implications for designing effective immunotherapy trials.

The role of myeloid cells in cancer therapies

“…The small-molecule compound DMXAA (also known as vadimezan), which was originally developed as a tumour-vascular disrupting agent, targets STING in mice 204 . Clinical trial results were disappointing but may be explained by the finding that human STING has an amino acid substitution that makes it insensitive to DMXAA 204 Intriguingly, the absence of STING also improves tumour control and CD8 + T cell activity in a mouse model of lung cancer 205 .…”

The host STING pathway at the interface of cancer and immunity

“…DNA sensing by the STING pathway can also mediate immune regulatory responses by induction of IFN-stimulated genes (ISG) with immunoregulatory functions like IDO (67). It has been shown that stimulation of the STING pathway in myeloid DCs using DNA nanoparticles induces IDO, which activate Tregs to promote dominant inhibitory T cell regulation (68,69). These data suggest that activation of the STING pathway can induce immune suppressive factors in the tumor microenvironment; thus, an appropriate level of STING pathway activation may be required for optimal antitumor effects.…”

Innate immune signaling and regulation in cancer immunotherapy

“…It also has been reported in the context of a non-immunogenic transplantable tumor that deficiency of STING increases tumor protection. In this model, activation of STING by DNA or STING agonists promoted tolerogenic responses by induction of indoleamine 2,3 dioxygenase (IDO), which activated Tregs to promote dominant inhibitory T cell regulation [65,66]. A recent study has linked the activation of STING and production of inflammatory cytokines to brain metastasis and chemoresistance [63].…”