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

Henrique Lemos, Eslam Mohamed, Lei Huang, Rong Ou, Gabriela Pacholczyk, Ali S. Arbab, David Munn, Andrew L. Mellor

Research output: Contribution to journalArticle

61 Citations (Scopus)

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 myeloidderived 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.

Original languageEnglish (US)
Pages (from-to)2076-2081
Number of pages6
JournalCancer Research
Volume76
Issue number8
DOIs
StatePublished - Apr 15 2016

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Interferons
Growth
Lewis Lung Carcinoma
Genes
Neoplasms
Tumor Microenvironment
Carcinogenesis
Lymph Nodes
T-Lymphocytes
DNA
Experimental Melanomas
Thymoma
Innate Immunity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation. / Lemos, Henrique; Mohamed, Eslam; Huang, Lei; Ou, Rong; Pacholczyk, Gabriela; Arbab, Ali S.; Munn, David; Mellor, Andrew L.

In: Cancer Research, Vol. 76, No. 8, 15.04.2016, p. 2076-2081.

Research output: Contribution to journalArticle

Lemos, Henrique ; Mohamed, Eslam ; Huang, Lei ; Ou, Rong ; Pacholczyk, Gabriela ; Arbab, Ali S. ; Munn, David ; Mellor, Andrew L. / STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation. In: Cancer Research. 2016 ; Vol. 76, No. 8. pp. 2076-2081.
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AB - 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 myeloidderived 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.

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