RESUMO
Hormone receptor-positive breast cancer (HR+) is immunologically cold and has not benefited from advances in immunotherapy. In contrast, subsets of triple-negative breast cancer (TNBC) display high leukocytic infiltration and respond to checkpoint blockade. CD8+ T cells, the main effectors of anticancer responses, recognize MHC I-associated peptides (MAPs). Our work aimed to characterize the repertoire of MAPs presented by HR+ and TNBC tumors. Using mass spectrometry, we identified 57,094 unique MAPs in 26 primary breast cancer samples. MAP source genes highly overlapped between both subtypes. We identified 25 tumor-specific antigens (TSAs) mainly deriving from aberrantly expressed regions. TSAs were most frequently identified in TNBC samples and were more shared among The Cancer Genome Atlas (TCGA) database TNBC than HR+ samples. In the TNBC cohort, the predicted number of TSAs positively correlated with leukocytic infiltration and overall survival, supporting their immunogenicity in vivo. We detected 49 tumor-associated antigens (TAAs), some of which derived from cancer-associated fibroblasts. Functional expansion of specific T cell assays confirmed the in vitro immunogenicity of several TSAs and TAAs. Our study identified attractive targets for cancer immunotherapy in both breast cancer subtypes. The higher prevalence of TSAs in TNBC tumors provides a rationale for their responsiveness to checkpoint blockade.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Antígenos de Neoplasias/genética , Imunoterapia/métodos , Linfócitos T CD8-Positivos/patologiaRESUMO
Insulin resistance is a component of the pathophysiology of both type 2 diabetes and gestational diabetes mellitus (GDM), but is also characteristic of normal glycemic physiology during pregnancy. In recent years, many studies have tried to understand determinants of insulin resistance in normal pregnancy and GDM, revealing that the placenta is capable of secreting many cytokines and hormones, classically considered as adipokines. More specifically, it appears that leptin and TNFα could be implicated in gestational insulin resistance and GDM pathophysiology. In addition, the maternal metabolic milieu was also identified as a key determinant of later insulin resistance in offspring, a phenomenon often described as 'fetal programming'. This article reviews the established risk factors and the more novel suspected biomarkers involved in maternal insulin resistance during pregnancy as well as the maternal and early life determinants of insulin resistance in offspring later in their life. We are also highlighting recent reports of the potential mechanisms involved in 'programming' of insulin resistance such as epigenetic modulation.
Assuntos
Resistência à Insulina/fisiologia , Adipocinas/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Gestacional/genética , Diabetes Gestacional/metabolismo , Diabetes Gestacional/patologia , Feminino , Humanos , Resistência à Insulina/genética , GravidezRESUMO
MHC-I-associated peptides deriving from non-coding genomic regions and mutations can generate tumor-specific antigens, including neoantigens. Quantifying tumor-specific antigens' RNA expression in malignant and benign tissues is critical for discriminating actionable targets. We present BamQuery, a tool attributing an exhaustive RNA expression to MHC-I-associated peptides of any origin from bulk and single-cell RNA-sequencing data. We show that many cryptic and mutated tumor-specific antigens can derive from multiple discrete genomic regions, abundantly expressed in normal tissues. BamQuery can also be used to predict MHC-I-associated peptides immunogenicity and identify actionable tumor-specific antigens de novo.