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

Lookup NU author(s): Dr Henrique De Paula Lemos, Dr Lei Huang, Dr Rong Ou, Professor Andrew Mellor

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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 overcame this state to enhance tumor immunogenicity. 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.


Publication metadata

Author(s): Lemos H, Mohamed E, Huang L, Ou R, Pacholczyk G, Arbab AS, Munn D, Mellor A

Publication type: Article

Publication status: Published

Journal: Cancer Research

Year: 2016

Volume: 76

Issue: 8

Pages: 2076-2081

Print publication date: 15/04/2016

Online publication date: 10/03/2016

Acceptance date: 10/02/2016

ISSN (print): 0008-5472

ISSN (electronic): 1538-7445

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/0008-5472.CAN-15-1456

DOI: 10.1158/0008-5472.CAN-15-1456

PubMed id: 26964621


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