Trends in Immunology
ReviewSpecial Issue: Immunity and CancerThe STING pathway and the T cell-inflamed tumor microenvironment
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
References (76)
- et al.
Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes?
Curr. Opin. Immunol.
(2007) Subtype-dependent prognostic relevance of an interferon-induced pathway metagene in node-negative breast cancer
Mol. Oncol.
(2014)Gene expression profiles of inflammatory breast cancer: correlation with response to neoadjuvant chemotherapy and metastasis-free survival
Ann. Oncol.
(2014)Type I interferon response and innate immune sensing of cancer
Trends Immunol.
(2013)Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING
Mol. Cell
(2013)STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors
Immunity
(2014)Structure–function analysis of STING activation by c[G(2′,5′)pA(3′,5′)p] and targeting by antiviral DMXAA
Cell
(2013)Targeting the tumor microenvironment with interferon-beta bridges innate and adaptive immune responses
Cancer Cell
(2014)STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors
Immunity
(2014)F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells
Immunity
(2012)