Browse by author
Lookup NU author(s): Dr Henrique De Paula LemosORCiD, Dr Lei HuangORCiD, Dr Rong Ou, Emeritus Professor Andrew MellorORCiD
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
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.
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
Altmetrics provided by Altmetric
