Immunopeptidomic Profiling of HLA‐A2‐Positive Triple Negative Breast Cancer Identifies Potential Immunotherapy Target Antigens

Ternette, Nicola; Mjm., Olde Nordkamp; Müller, Julius; Anderson, Amanda P.; Nicastri, Annalisa; Avs., Hill; Kessler, Benedikt M.; Li, Demin

doi:10.1002/pmic.201700465

Cited by 37 publications

(34 citation statements)

References 46 publications

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“…IL-32 increased migration and invasion capacities of TNBC cells [64] and promoted TNBC cell growth [65]. In addition, IL-32 is a potential immunotherapy target antigen in HLA-A2-positive TNBC [66]. Based on these results, a high level of IL32 in TNBC (Figure 2) may be involved in aggressiveness of TNBC despite unclear direct relationship between SAA and IL32.…”

Section: Discussionmentioning

confidence: 99%

Serum amyloid A predisposes inflammatory tumor microenvironment in triple negative breast cancer

et al. 2019

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Acute-phase proteins (APPs) are associated with a variety of disorders such as infection, inflammatory diseases, and cancers. The signature profile of APPs in breast cancer (BC) is poorly understood. Here, we identified serum amyloid A (SAA) for proinflammatory predisposition in BC through the signature profiles of APPs, interleukin (IL) and tumor necrosis factor (TNF) superfamily using publicly available datasets of tumor samples and cell lines. Triple-negative breast cancer (TNBC) subtype highly expressed SAA1/2 compared to HER2, luminal A (LA) and luminal B (LB) subtypes. IL1A, IL1B, IL8/CXCL8, IL32 and IL27RA in IL superfamily and CD70, TNFSF9 and TNFRSF21 in TNF superfamily were highly expressed in TNBC compared to other subtypes. SAA is restrictedly regulated by nuclear factor (NF)-κB and IL-1β, an NF-κB activator highly expressed in TNBC, increased the promoter activity of SAA1 in human TNBC MDA-MB231 cells. Interestingly, two κB-sites contained in SAA1 promoter were involved, and the proximal region (−96/−87) was more critical than the distal site (−288/−279) in regulating IL-1β-induced SAA1. Among the SAA receptors, TLR1 and TLR2 were highly expressed in TNBC. Cu-CPT22, TLR1/2 antagonist, abrogated IL-1β-induced SAA1 promoter activity. In addition, SAA1 induced IL8/CXCL8 promoter activity, which was partially reduced by Cu-CPT22. Notably, SAA1/2, TLR2 and IL8/CXCL8 were associated with a poor overall survival in mesenchymal-like TNBC. Taken together, IL-1-induced SAA via NF-κB-mediated signaling could potentiate an inflammatory burden, leading to cancer progression and high mortality in TNBC patients.

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Section: Discussionmentioning

confidence: 99%

Serum amyloid A predisposes inflammatory tumor microenvironment in triple negative breast cancer

et al. 2019

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“…Improvements in sensitivity and speed of this instrumentation now make peptidome profiling of HLA-bound peptides relatively routine and have opened up the possibility to work with limited patient-derived material ( 90 , 91 ). Such analysis also allows for unambiguous definition of posttranslational modifications of epitopes ( 92 – 95 ) or from proteome extracts ( 19 , 96 – 98 ) of patient-derived material. To date, characterization of the HLA class I–bound peptides from human β-cells has been limited, primarily due to difficulties in obtaining sufficient material ( 20 ).…”

Section: Novel Technologies In T-cell Response and Autoantigen Identimentioning

confidence: 99%

The Evolving Landscape of Autoantigen Discovery and Characterization in Type 1 Diabetes

2019

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Type 1 diabetes (T1D) is an autoimmune disease that is caused, in part, by T cell–mediated destruction of insulin-producing β-cells. High risk for disease, in those with genetic susceptibility, is predicted by the presence of two or more autoantibodies against insulin, the 65-kDa form of glutamic acid decarboxylase (GAD65), insulinoma-associated protein 2 (IA-2), and zinc transporter 8 (ZnT8). Despite this knowledge, we still do not know what leads to the breakdown of tolerance to these autoantigens, and we have an incomplete understanding of T1D etiology and pathophysiology. Several new autoantibodies have recently been discovered using innovative technologies, but neither their potential utility in monitoring disease development and treatment nor their role in the pathophysiology and etiology of T1D has been explored. Moreover, neoantigen generation (through posttranslational modification, the formation of hybrid peptides containing two distinct regions of an antigen or antigens, alternative open reading frame usage, and translation of RNA splicing variants) has been reported, and autoreactive T cells that target these neoantigens have been identified. Collectively, these new studies provide a conceptual framework to understand the breakdown of self-tolerance, if such modifications occur in a tissue- or disease-specific context. A recent workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases brought together investigators who are using new methods and technologies to identify autoantigens and characterize immune responses toward these proteins. Researchers with diverse expertise shared ideas and identified resources to accelerate antigen discovery and the detection of autoimmune responses in T1D. The application of this knowledge will direct strategies for the identification of improved biomarkers for disease progression and treatment response monitoring and, ultimately, will form the foundation for novel antigen-specific therapeutics. This Perspective highlights the key issues that were addressed at the workshop and identifies areas for future investigation.

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“…This was the first report showing that IL-32β plays a role in the regulation of breast cancer cell metabolism. A recent report suggested that IL-32 is a prospective therapeutic target for triple negative breast cancer, since IL-32 was more highly expressed in cancer tissue from patients with triple negative breast cancer (53), implying a critical role of IL-32 in the progression of the breast cancer.…”

Section: Role Of Il-32 In Other Types Of Cancermentioning

confidence: 99%

Interleukin-32: Frenemy in cancer?

Han

Yang

2019

BMB Rep.

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Interleukin-32 (IL-32) was originally identified in natural killer (NK) cells activated by IL-2 in 1992. Thus, it was named NK cell transcript 4 (NK4) because of its unknown function at that time. The function of IL-32 has been elucidated over the last decade. IL-32 is primarily considered to be a booster of inflammatory reactions because it is induced by pro-inflammatory cytokines and stimulates the production of those cytokines and vice versa . Therefore, many studies have been devoted to studying the roles of IL-32 in inflammation-associated cancers, including gastric, colon cancer, and hepatocellular carcinoma. At the same time, roles of IL-32 have also been discovered in other cancers. Collectively, IL-32 fosters the tumor progression by nuclear factor-κB (NF-κB)-mediated cytokines and metalloproteinase production, as well as stimulation of differentiation into immunosuppressive cell types in some cancer types. However, it is also able to induce tumor cell apoptosis and enhance NK and cytotoxic T cell sensitivity in other cancer types. In this review, we will address the function of each IL-32 isoform in different cancer types studied to date, and suggest further strategies to comprehensively elucidate the roles of IL-32 in a context-dependent manner.

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Immunopeptidomic Profiling of HLA‐A2‐Positive Triple Negative Breast Cancer Identifies Potential Immunotherapy Target Antigens

Cited by 37 publications

References 46 publications

Serum amyloid A predisposes inflammatory tumor microenvironment in triple negative breast cancer

Serum amyloid A predisposes inflammatory tumor microenvironment in triple negative breast cancer

The Evolving Landscape of Autoantigen Discovery and Characterization in Type 1 Diabetes

Interleukin-32: Frenemy in cancer?

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