Epigenetic repression of STING by MYC promotes immune evasion and resistance to immune checkpoint inhibitors in triple negative breast cancer.
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE196325 | GEO | 2022/03/01
REPOSITORIES: GEO
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Project description:The MYC oncogene is frequently amplified in triple negative breast cancer (TNBC). Here, we show that MYC suppression induces immune-related hallmark gene set signatures and tumor infiltrating T cells in MYC-hyperactivated TNBCs. Mechanistically, MYC repressed stimulator of interferon genes (STING) expression via direct binding to the STING enhancer region, resulting in downregulation of the T cell chemokines CCL5, CXCL10 and CXCL11. In primary and metastatic TNBC cohorts, tumors with high MYC expression or activity exhibited low STING expression. Using a CRISPR-mediated enhancer perturbation approach, we demonstrated that MYC-driven immune evasion is mediated by STING repression. STING repression induced resistance to PD-L1 blockade in mouse models of TNBC. Finally, a small molecule inhibitor of MYC combined with PD-L1 blockade elicited a durable response in immune-cold TNBC with high MYC levels, suggesting a strategy to restore PD-L1 inhibitor sensitivity in MYC-overexpressing TNBC.
2022-03-01 | GSE196324 | GEO
Project description:The MYC oncogene is frequently amplified in triple negative breast cancer (TNBC). Here, we show that MYC suppression induces immune-related hallmark gene set signatures and tumor infiltrating T cells in MYC-hyperactivated TNBCs. Mechanistically, MYC repressed stimulator of interferon genes (STING) expression via direct binding to the STING enhancer region, resulting in downregulation of the T cell chemokines CCL5, CXCL10 and CXCL11. In primary and metastatic TNBC cohorts, tumors with high MYC expression or activity exhibited low STING expression. Using a CRISPR-mediated enhancer perturbation approach, we demonstrated that MYC-driven immune evasion is mediated by STING repression. STING repression induced resistance to PD-L1 blockade in mouse models of TNBC. Finally, a small molecule inhibitor of MYC combined with PD-L1 blockade elicited a durable response in immune-cold TNBC with high MYC levels, suggesting a strategy to restore PD-L1 inhibitor sensitivity in MYC-overexpressing TNBC.
2022-03-01 | GSE196323 | GEO
Project description:Epigenetic repression of STING by MYC promotes immune evasion and resistance to immune checkpoint inhibitors in triple negative breast cancer.
| PRJNA804401 | ENA
Project description:Few patients with triple negative breast cancer (TNBC) benefit from immune checkpoint inhibitors with complete and durable remissions being quite rare. Oncogenes can regulate tumor immune infiltration, however whether oncogenes dictate diminished response to immunotherapy and whether these effects are reversible remains poorly understood. Here, we report that TNBCs with elevated MYC expression are resistant to immune checkpoint inhibitor therapy. Using mouse models and patient data, we show that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, mice experience tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and when strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.
| S-EPMC9237085 | biostudies-literature
Project description:Epigenetic repression of STING by MYC promotes immune evasion and resistance to immune checkpoint inhibitors in triple negative breast cancer [CHIP-seq]
| PRJNA804406 | ENA
Project description:Epigenetic repression of STING by MYC promotes immune evasion and resistance to immune checkpoint inhibitors in triple negative breast cancer [RNA-seq]
| PRJNA804407 | ENA
Project description:Immunotherapy has emerged as the fifth pillar of cancer treatment alongside surgery, radiotherapy, chemotherapy, and targeted therapy. Immune checkpoint inhibitors are the current superheroes of immunotherapy, unleashing a patient's own immune cells to kill tumors and revolutionizing cancer treatment in a variety of cancers. Although breast cancer was historically believed to be immunologically silent, treatment with immune checkpoint inhibitors has been shown to induce modest responses in metastatic breast cancer. Given the inherent heterogeneity of breast tumors, this raised the question whether certain breast tumors might benefit more from immune-based interventions and which cancer cell-intrinsic and/or microenvironmental factors define the likelihood of inducing a potent and durable anti-tumor immune response. In this review, we will focus on triple negative breast cancer as immunogenic breast cancer subtype, and specifically discuss the relevance of tumor mutational burden, the plethora and diversity of tumor infiltrating immune cells in addition to the immunoscore, the presence of immune checkpoint expression, and the microbiome in defining immune checkpoint blockade response. We will highlight the current immune checkpoint inhibitor treatment options, either as monotherapy or in combination with standard-of-care treatment modalities such as chemotherapy and targeted therapy. In addition, we will look into the potential of immunotherapy-based combination strategies using immune checkpoint inhibitors to enhance both innate and adaptive immune responses, or to establish a more immune favorable environment for cancer vaccines. Finally, the review will address the need for unambiguous predictive biomarkers as one of the main challenges of immune checkpoint blockade. To conclude, the potential of immune checkpoint blockade for triple negative breast cancer treatment could be enhanced by exploration of aforementioned factors and treatment strategies thereby providing promising future prospects.
| S-EPMC7947906 | biostudies-literature
Project description:The tumour stroma regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple-negative breast cancers (TNBCs) remains poorly understood, limiting the development of stromal-targeted therapies. Single cell RNA-sequencing of five TNBCs revealed two cancer-associated fibroblast (CAF) and two perivascular-like (PVL) subpopulations. CAFs clustered into two states, the first with features of myofibroblasts and the second characterised by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships and functional properties in regulating the extracellular matrix. Using cell-signalling predictions, we provide evidence that stromal-immune crosstalk acts via a diverse array of immunoregulatory molecules. Importantly, the investigation of gene signatures from inflammatory-CAFs and differentiated-PVL cells in independent TNBC patient cohorts revealed strong associations with cytotoxic T-cell dysfunction and exclusion, respectively. Such insights present promising candidates to further investigate for new therapeutic strategies in the treatment of TNBCs.
| S-SCDT-EMBOJ-2019-104063 | biostudies-other
Project description:Background:Triple-negative breast cancer (TNBC) represents an aggressive breast cancer subtype with historically poor overall outcomes, due primarily to a lack of effective targeted agents. Chemotherapy has been the primary treatment approach, although immune checkpoint inhibitors (ICIs) are currently being investigated to improve patient outcomes. This review examines the clinical implications of current evidence on the use of ICIs for the treatment of metastatic TNBC. Methods:Our systematic search identified two phase?III and five phase?I/II trials reporting on the efficacy of ICIs used as monotherapy or combined with chemotherapy for the treatment of metastatic TNBC. Results:The phase?III IMpassion 130 trial showed a significant improvement in median progression-free survival in the intent-to-treat (net 1.7?months, p?=?0.002) and PD-L1-positive populations (net 2.5?months, p?<?0.001) for the addition of first-line atezolizumab versus placebo to nab-paclitaxel in metastatic TNBC. Although median overall survival was not significantly improved in patients receiving atezolizumab overall [net 2.3?months, hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.72-1.02, p?=?0.078], numerical improvements in the PD-L1-positive population were compelling (net 7.0?months, HR 0.71; 95% CI 0.54-0.93). Toxicity profiles were as expected, and no new safety signals were observed. Pembrolizumab monotherapy did not significantly improve overall survival in similar patients that had received prior treatment in KEYNOTE-119. Conclusions:Atezolizumab plus nab-paclitaxel represents a potential new first-line standard of care for patients with metastatic PD-L1-positive TNBC. Other ICIs used as monotherapy, or combined with chemotherapy for advanced TNBC, as well as their use for earlier stage disease, are areas of ongoing investigation.
| S-EPMC7517981 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) have rapidly altered the treatment landscape for multiple tumor types, providing unprecedented survival in some patients. Despite the characteristic durability of response to ICI, unfortunately many patients with initial response will later develop acquired resistance. The current understanding of mechanisms of acquired resistance to ICIs is remarkably limited, perhaps restraining effective development of next-generation immunotherapies. Here, we examine the barriers to progress and emerging clinical reports interrogating acquired resistance with the goal to facilitate efforts to overcome acquired resistance to ICIs in the future.
| S-EPMC7182070 | biostudies-literature