Trends in Immunology
Volume 36, Issue 4, April 2015, Pages 250-256
Journal home page for Trends in Immunology

Review
Special Issue: Immunity and Cancer
The STING pathway and the T cell-inflamed tumor microenvironment

https://doi.org/10.1016/j.it.2015.02.003Get rights and content

Highlights

  • A T cell-inflamed tumor microenvironment is associated with benefit to immunotherapies.

  • The mechanism of endogenous T cell priming against tumor antigens has been elusive.

  • Mechanistic data indicate a crucial role for type I IFNs as a bridge to adaptive immunity.

  • Recent data implicate the host STING pathway in innate immune sensing of tumors.

A major subset of patients with advanced solid tumors show a spontaneous T cell-inflamed tumor microenvironment, which has prognostic import and is associated with clinical response to immunotherapies. As such, understanding the mechanisms governing the generation of spontaneous T cell responses in only a subset of patients is critical for advancing immunotherapeutic approaches further. Here, we discuss the characteristics of T cell-inflamed versus non-inflamed tumors, including a type I interferon (IFN) signature associated with T cell priming against tumor antigens. We review recent findings that have pointed towards the STING (stimulator of interferon genes) pathway of cytosolic DNA sensing as an important innate immune sensing mechanism driving type I IFN production in the tumor context. Knowledge of this pathway is guiding the further development of novel immunotherapeutic strategies.

Introduction

The molecular identification of tumor antigens has transformed the field of tumor immunology and cancer immunotherapy. While many initial antigens were defined that were shared between patients, such as those encoded by MAGE (melanoma antigen gene) family of genes [1], more recent work has revealed unique antigens that arise from point mutations in normal genes generated during the genomic instability that is part of the process of carcinogenesis 2, 3, 4, 5. Whole-exome sequencing of human cancers of various histologies has revealed that many tumors, especially those induced by carcinogens such as UV light or tobacco, contain hundreds or even thousands of non-synonymous mutations [6]. Therefore, the current thinking is that most tumors express some level of antigens that could theoretically be recognized by T cells of the immune system. Knowledge of these antigens combined with high-throughput genomics technologies has provided tools for analyzing patient tumor, blood, and lymphoid tissues for antigen-specific T cell populations and features of the host antitumor immune response, either spontaneous or in response to therapeutic interventions. Much of this work has culminated with the notion that features of the tumor microenvironment are crucial determinants of patient outcome. Therefore, an expanded effort in studying the immune phenotype of the tumor microenvironment has emerged.

In early-stage colorectal cancer, the presence of activated CD8+ T cells within the tumor and in the peritumoral stroma has been shown to have significant positive prognostic import 7, 8, 9. A subset of patients with other solid tumor histologies also appear to have a spontaneous T cell infiltrate that may have similar positive prognostic value. These include breast cancer, renal cell carcinoma, melanoma, ovarian cancer, and gastrointestinal stromal tumors (GIST) 10, 11, 12, 13, 14. A presumption is that a component of this T cell infiltrate includes tumor antigen-specific T cells that have been activated spontaneously in response to the growing tumor, perhaps through immune surveillance mechanisms [15]. This attempted host immune response, even if it does not eliminate the tumor completely, is thought to delay tumor progression and thus yield improved clinical outcome.

The fact that a subset of patients appear to generate a spontaneous antitumor immune response, while another major subset does not, has generated several important biologic questions that have implications for further refinement of cancer immunotherapies. One central mystery has been identifying the innate immune mechanisms that give rise to a spontaneous adaptive T cell response against tumor antigens in the absence of exogenous infection. Clues have been gleaned from human cancer gene expression profiling studies revealing an association between a type I IFN signature, T cell infiltration, and clinical outcome. This has allowed a focus on innate immune sensing pathways known to trigger type I IFN production that might represent crucial intermediate mechanistic steps. Before discussing these pathways in detail, the T cell-inflamed tumor microenvironment will be put into the context of our current understanding of the therapeutic efficacy of contemporary cancer immunotherapy approaches.

Section snippets

The T cell-inflamed versus non-T cell-inflamed tumor microenvironment in metastatic disease

The motivation for analyzing the tumor microenvironment in metastatic melanoma was initially derived from the hypothesis that resistance mechanisms downstream from T cell priming following vaccination against tumor antigens might be dominant and enable tumor escape 16, 17. To explore this question in patients, baseline biopsies of melanoma metastases were evaluated by gene expression profiling. It became clear that two major subsets of tumor microenvironment could be identified that were

Baseline T cell infiltration and therapeutic efficacy of checkpoint blockade

The original hypothesis in the context of melanoma vaccine studies was that the patients showing clinical benefit might have low expression of immune inhibitory mechanisms in the tumor microenvironment, whereas the resistant patients might show the highest expression. However, the opposite pattern was paradoxically observed. A baseline T cell-inflamed tumor microenvironment (that includes the presence of PD-L1, IDO, and Treg cells) was positively associated with clinical benefit from these

Mechanism of innate immune sensing driving spontaneous adaptive immunity: role of type I IFNs

Given the functional importance of spontaneous T cell priming against tumor-associated antigens as a predictive biomarker for clinical response to immunotherapies, understanding the mechanism by which this occurs has become paramount. In general, for productive T cell responses to be induced against specific antigens, dendritic cells (DCs) or other antigen-presenting cells (APCs) need to be activated by additional molecular entities. In the setting of pathogen infections, this is often mediated

The STING pathway as innate immune sensing to drive type I IFN production and adaptive immunity

Given the evidence indicating that I IFN production is necessary for optimal T cell priming against tumor antigens, a next crucial mechanistic question has been to identify the receptor system and putative ligands that trigger IFN-β production by host DCs in response to a growing tumor in vivo. Recent evidence has pointed toward a crucial role for the STING pathway in this process. STING is an adapter that is activated by cyclic dinucleotides generated by cyclic GMP-AMP synthase (cGAS), which

Therapeutic implications of the STING pathway in cancer

There are two major clinical implications of the findings that the host STING pathway is crucial for innate immune sensing of tumors. First, it seems likely that the ability of a cancer in an individual patient to support STING pathway activation is linked to the spontaneous generation of a T cell-inflamed tumor microenvironment. Because this phenotype is associated with improved prognosis of early-stage cancer patients, and also with clinical response to immunotherapies in the metastatic

Concluding remarks

As a relatively new area of investigation, numerous unanswered questions remain regarding the role of the STING pathway in antitumor immune response in vivo (Box 1). First, the mechanism by which DNA can be derived from dying tumor cells and gain access to the cytosol of host APCs is not yet understood. Free DNA alone does not activate DCs in vitro but requires the addition of Lipofectamine or another transfection reagent [59]. In principle, extracellular DNA would be degraded by DNase I in the

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