title: 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 induces 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). Although STING also induced IDO in tumor-draining lymph nodes (TDLN) 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 IL10 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 with native LLC tumors, STING signaling neither promoted 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. Furthermore, 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. Cancer Res; 76(8); 2076-81. ©2016 AACR.
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program and.
authors.forename: Henrique
authors.initials: H
authors.lastname: Lemos
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program and.
authors.forename: Eslam
authors.initials: E
authors.lastname: Mohamed
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program and Department of Radiology, Augusta University, Augusta, Georgia.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program and.
authors.forename: Rong
authors.initials: R
authors.lastname: Ou
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program and.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Pacholczyk
authors.affiliation: Tumor Angiogenesis Program, Cancer Center, Augusta University, Augusta. Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Arbab
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program and Department of Pediatrics, Augusta University, Augusta, Georgia.
authors.forename: David
authors.initials: D
authors.lastname: Munn
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program and Department of Medicine, Augusta University, Augusta, Georgia. amellor@gru.edu.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D013945:Thymoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000276:immunology; D000099197:STING Protein
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008565:Membrane Proteins; C530855:Sting1 protein, mouse; D000099197:STING Protein