Role of Senescence and Aging in SARS-CoV-2 Infection and COVID-19 Disease

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic associated with substantial morbidity and mortality worldwide, with particular risk for severe disease and mortality in the elderly population. SARS-CoV-2 infection is driven by a pathological hyperinflammatory response which results in a dysregulated immune response. Current advancements in aging research indicates that aging pathways have fundamental roles in dictating healthspan in addition to lifespan. Our review discusses the aging immune system and highlights that senescence and aging together, play a central role in COVID-19 pathogenesis. In our review, we primarily focus on the immune system response to SARS-CoV-2 infection, the interconnection between severe COVID-19, immunosenescence, aging, vaccination, and the emerging problem of Long-COVID. We hope to highlight the importance of identifying specific senescent endotypes (or “sendotypes”), which can used as determinants of COVID-19 severity and mortality. Indeed, identified sendotypes could be therapeutically exploited for therapeutic intervention. We highlight that senolytics, which eliminate senescent cells, can target aging-associated pathways and therefore are proving attractive as potential therapeutic options to alleviate symptoms, prevent severe infection, and reduce mortality burden in COVID-19 and thus ultimately enhance healthspan

Prognostic value of the 6-gene OncoMasTR test in hormone receptor–positive HER2-negative early-stage breast cancer: Comparative analysis with standard clinicopathological factors

Aim: The aim of the study was to assess the prognostic performance of a 6-gene molecular score (OncoMasTR Molecular Score [OMm]) and a composite risk score (OncoMasTR Risk Score [OM]) and to conduct a within-patient comparison against four routinely used molecular and clinicopathological risk assessment tools: Oncotype DX Recurrence Score, Ki67, Nottingham Prognostic Index and Clinical Risk Category, based on the modified Adjuvant! Online definition and three risk factors: patient age, tumour size and grade. Methods: Biospecimens and clinicopathological information for 404 Irish women also previously enrolled in the Trial Assigning Individualized Options for Treatment [Rx] were provided by 11 participating hospitals, as the primary objective of an independent translational study. Gene expression measured via RT-qPCR was used to calculate OMm and OM. The prognostic value for distant recurrence-free survival (DRFS) and invasive disease-free survival (IDFS) was assessed using Cox proportional hazards models and Kaplan-Meier analysis. All statistical tests were two-sided ones. Results: OMm and OM (both with likelihood ratio statistic [LRS] P Discussion: Both OncoMasTR scores were significantly prognostic for DRFS and IDFS and provided additional prognostic information to the molecular and clinicopathological risk factors/tools assessed. OM was also the most accurate risk classification tool for identifying DR. A concise 6-gene signature with superior risk stratification was shown to increase prognosis reliability, which may help clinicians optimise treatment decisions. Trial registration: ClinicalTrials.gov NCT02050750 NCT00310180.</p

Mapping the immune landscape in metastatic melanoma reveals localized cell-cell interactions that predict immunotherapy response

While immune checkpoint–based immunotherapy (ICI) shows promising clinical results in patients with cancer, only a subset of patients responds favorably. Response to ICI is dictated by complex networks of cellular interactions between malignant and nonmalignant cells. Although insights into the mechanisms that modulate the pivotal antitumoral activity of cytotoxic T cells (Tcy) have recently been gained, much of what has been learned is based on single-cell analyses of dissociated tumor samples, resulting in a lack of critical information about the spatial distribution of relevant cell types. Here, we used multiplexed IHC to spatially characterize the immune landscape of metastatic melanoma from responders and nonresponders to ICI. Such high-dimensional pathology maps showed that Tcy gradually evolve toward an exhausted phenotype as they approach and infiltrate the tumor. Moreover, a key cellular interaction network functionally linked Tcy and PD-L1(+) macrophages. Mapping the respective spatial distributions of these two cell populations predicted response to anti-PD-1 immunotherapy with high confidence. These results suggest that baseline measurements of the spatial context should be integrated in the design of predictive biomarkers to identify patients likely to benefit from ICI. SIGNIFICANCE: This study shows that spatial characterization can address the challenge of finding efficient biomarkers, revealing that localization of macrophages and T cells in melanoma predicts patient response to ICI. See related commentary by Smalley and Smalley, p. 319

A translational effort to identify prognostic and predictive biomarkers in pancreatic cancer among RBM3-regulated genes

Background Pancreatic cancer has a dismal prognosis and clinical protocols are still lacking predictive biomarkers. RNA-binding motif protein 3 (RBM3) has emerged as a promising biomarker in several solid cancers, including pancreatic cancer.. High RBM3 expression in human tumors has been associated with good response to chemotherapy, as well as to confer increased chemosensitivity in vitro. The aim of this study was to identify RBM3-regulated genes in pancreatic cells in vitro, and further interrogate their potential utility as prognostic and predictive biomarkers in a translational setting. Methods Next generation RNA-sequencing was applied to compare gene expression between MIAPaCa-2 cells with siRNA-downregulated RBM3 and control cells. Single genes with the strongest association to RBM3 were further selected by gene set enrichment analysis, and their prognostic value in pancreatic cancer was examined in The Cancer Genome Atlas (TCGA). The most promising biomarker candidates with well-validated antibodies were then analyzed by immunohistochemistry in tissue microarrays with tumors from a consecutive, retrospective cohort of 175 patients with periampullary and pancreatic adenocarcinoma. Results MIAPaCa-2 cells with downregulated RBM3 displayed 21 differentially expressed genes (p<0.01). One of the top downregulated genes was PDS cohesion associated factor A (PDS5A) encoding a protein involved in sister chromatid cohesion. PDS5A protein expression was reduced in siRBM3-treated MIAPaCa-2 cells compared to control cells. High PDS5A mRNA expression was significantly associated with a reduced survival in pancreatic cancer in the TCGA (n=176, p=0.026). High PDS5A protein expression in the separate cohort was significantly associated with a poor prognosis but predictive of improved response to adjuvant chemotherapy in KRAS-mutated, but not wild-type, pancreatobiliary-type tumors (p for interaction=0.043). Conclusions Here, we provide the first report of the expression of PDS5A in pancreatic and periampullary cancer, suggesting its potential utility as a prognostic and predictive biomarker. Further studies to unravel the underlying mechanisms are encouraged