Comprehensive evaluation of methodology to assess abundance of immune infiltrates in breast cancer

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Comprehensive evaluation of methods to assess overall and cell-specific immune infiltrates in breast cancer

Background: Breast cancer (BC) immune infiltrates play a critical role in tumor progression and response to treatment. Besides stromal tumor infiltrating lymphocytes (sTILs) which have recently reached level 1B evidence as a prognostic marker in triple negative BC, a plethora of methods to assess immune infiltration exists, and it is unclear how these compare to each other and if they can be used interchangeably. Methods: Two experienced pathologists scored sTIL, intra-tumoral TIL (itTIL), and 6 immune cell types (CD3+, CD4+, CD8+, CD20+, CD68+, FOXP3+) in the International Cancer Genomics Consortium breast cancer cohort using hematoxylin and eosin-stained (n = 243) and immunohistochemistry-stained tissue microarrays (n = 254) and whole slides (n = 82). The same traits were evaluated using transcriptomic- and methylomic-based deconvolution methods or signatures. Results: The concordance correlation coefficient (CCC) between pathologists for sTIL was very good (0.84) and for cell-specific immune infiltrates slightly lower (0.63-0.66). Comparison between tissue microarray and whole slide pathology scores revealed systematically higher values in whole slides (ratio 2.60-5.98). The Spearman correlations between microscopic sTIL and transcriptomic- or methylomic-based assessment of immune infilt

A pan-cancer clinical platform to predict immunotherapy outcomes and prioritize immuno-oncology combinations in early-phase trials

Immunooncology; Predictive biomarkers; Tumor microenvironmentInmunooncología; Biomarcadores predictivos; Microambiente tumoralImmunooncologia; Biomarcadors predictius; Microambient tumoralBackground Immunotherapy is effective, but current biomarkers for patient selection have proven modest sensitivity. Here, we developed VIGex, an optimized gene signature based on the expression level of 12 genes involved in immune response with RNA sequencing. Methods We implemented VIGex using the nCounter platform (Nanostring) on a large clinical cohort encompassing 909 tumor samples across 45 tumor types. VIGex was developed as a continuous variable, with cutoffs selected to detect three main categories (hot, intermediate-cold and cold) based on the different inflammatory status of the tumor microenvironment. Findings Hot tumors had the highest VIGex scores and exhibited an increased abundance of tumor-infiltrating lymphocytes as compared with the intermediate-cold and cold. VIGex scores varied depending on tumor origin and anatomic site of metastases, with liver metastases showing an immunosuppressive tumor microenvironment. The predictive power of VIGex-Hot was observed in a cohort of 98 refractory solid tumor from patients treated in early-phase immunotherapy trials and its clinical performance was confirmed through an extensive metanalysis across 13 clinically annotated gene expression datasets from 877 patients treated with immunotherapy agents. Last, we generated a pan-cancer biomarker platform that integrates VIGex categories with the expression levels of immunotherapy targets under development in early-phase clinical trials. Conclusions Our results support the clinical utility of VIGex as a tool to aid clinicians for patient selection and personalized immunotherapy interventions.A.H.C. would like to acknowledge fellowship funding from the Spanish Society of Medical Oncology (SEOM), CRIS Contra el Cancer and Hold'em For Life Oncology Fellowship. This research has been funded by the Comprehensive Program of Cancer Immunotherapy & Immunology II (CAIMI-II) supported by the BBVA Foundation (grant 53/2021) and the 2020–2021 Division of Medical Oncology and Hematology (DMOH) Fellowship award at Princess Margaret Cancer Centre. VHIO would like to acknowledge the Cellex Foundation for providing research facilities and equipment and the CERCA Programme from the Generalitat de Catalunya for their support of this research. Authors from VHIO acknowledge the State Agency for Research (Agencia Estatal de Investigación) for providing financial support as a Center of Excellence Severo Ochoa (CEX2020-001024-S/AEI/10.13039/501100011033). A.V. was the recipient of a project award from the FAECC (AVP/18/AECC/3219) and received funding from the Advanced Molecular Diagnostic (DIAMAV) program from the FERO Foundation. Graphical abstract was created with BioRender.com. Diagram in Figure 3B was created with SankeyMATIC (sankeymatic.com)

Immune infiltration in invasive lobular breast cancer

Background: Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer after invasive ductal cancer (IDC). Here, we aimed at evaluating the prevalence, levels and composition of tumor infiltrating lymphocytes (TIL) and their association with clinico-pathological, and outcome variables in ILC, and to compare it with IDC. Methods: We considered two patient series with TIL data: a multi-centric retrospective series (n=614) and the BIG 02-98 study (n=149 ILC and 807 IDC). We compared immune subsets identified by immuno-histochemistry in the ILC (n=159) and IDC (n=468) patients from the Nottingham series, as well as the CIBERSORT immune profiling of the ILC (n=98) and IDC (n=388) METABRIC and TCGA patients. All ILC/IDC comparisons were done in ER-positive/HER2-negative tumors. All statistical tests were two-sided. Results: TIL levels were statistically significantly lower in ILC compared to IDC (fold change =0.79; 95%CI: 0.70-0.88, P<.001). In ILC, high TIL levels were associated with young age, lymph node involvement, and high proliferative tumors. In the univariable analysis, high TIL levels were associated with worse prognosis in the retrospective and BIG 02-98 lobular series, although it did not reach statistical significance in the latter. The Nottingham series revealed that the levels of intra-tumoral but not total CD8+ were statistically significantly lower in ILC compared to IDC. Comparison of the CIBERSORT profiles highlighted statistically significant differences in terms of immune composition. Conclusion: This study shows differences between the immune infiltrates of ER-positive/HER2-negative ILC and IDC in terms of prevalence, levels, localization, composition, and clinical associations

Genomic aberrations associated with triple-negative breast cancer (TNBC) molecular subtypes based on Lehmann classification.

Le cancer du sein (BC) est la tumeur maligne la plus répandue et la deuxièmecause de mortalité due au cancer chez les femmes dans le monde. Les récentsprogrès en matière de diagnostic précoce et de traitements anticancéreux efficaces enBC ont nettement amélioré la survie des patientes atteintes de cette maladie.Cependant, le cancer du sein triple négatif (TNBC), qui est le sous-type le plus agressifde cancer du sein, est associé à un taux élevé de récidive et à un plus mauvaispronostic. Les TNBC, représentant 10 à 20% des cancers du sein, sont définis parl’absence des récepteurs à l’oestrogène (ER), à la progestérone (PR) ainsi que durécepteur aux facteurs de croissance épidermiques (HER2). À ce jour, les options detraitement pour les patientes atteintes d’un TNBC restent principalement limitées à lachimiothérapie. Les premières études cliniques évaluant les inhibiteurs de points decontrôle immunitaire PD-1/PD-L1 dans le cancer du sein ont démontré un effetfavorable dans le traitement des TNBC. La combinaison anti-PD-L1 et chimiothérapieest depuis peu approuvée comme thérapie dans le TNBC à un stade avancé.Cependant, à l'instar d'autres thérapies ciblées, une proportion importante de patientesne tire pas profit de cette approche. Une meilleure caractérisation de l’hétérogénéitéde la tumeur et de son microenvironnement devient donc nécessaire afin d’optimiserla stratification des patientes atteintes d’un TNBC afin d’élaborer des stratégies detraitement personnalisées.En 2011, les avancées dans les technologies de séquençage à haut débit ontpermis de mettre en évidence l’hétérogénéité présente au sein de cette maladie endistinguant la présence de six sous-types moléculaires au niveau transcriptomique :deux sous-types basal-like (BL1 & BL2), un sous-type immunomodulateur (IM), unsous-type luminal androgen receptor (LAR), un sous-type mesenchymal (M) et unsous-type mesenchymal stem-like (MSL). L’objectif de cette thèse consiste à étudierces sous-types moléculaires en fonction des informations clinico-pathologiques, de lasurvie mais aussi des altérations génomiques et transcriptomiques obtenues au seindes larges cohortes rétrospectives de patientes TNBC.Dans la première partie de ce travail, nous avons mis en évidence l’importantehétérogénéité des TNBC au regard de leur classification moléculaire. Notre travailixdémontre d’importantes distinctions tant au niveau génomique qu’au niveautranscriptomique entre les sous-types moléculaires. Cette hétérogénéité entre lessous-types moléculaires se retrouve aussi au niveau des caractéristiques clinicopathologiques,de l’évolution clinique et en matière de pronostic de survie.La seconde partie de cette thèse consiste en une caractérisation del’hétérogénéité du microenvironnement tumoral ouvrant de possibles applicationsimmuno-thérapeutiques pour traiter cette maladie. En comparaison aux autres soustypesde cancer du sein, les TNBC sont caractérisés par un taux élevé d’infiltrationlymphocytaire et l’immunothérapie est apparue comme une stratégie de traitementprometteuse. Les dernières études cliniques ont démontré des résultatsencourageants pour les inhibiteurs de points de contrôle immunitaire en monothérapieet en combinaison avec de la chimiothérapie. Dans le but de mieux sélectionner lespatients qui pourraient bénéficier de ces traitements, nous avons étudié différentsprocessus reflétant le microenvironnementDoctorat en Sciences biomédicales et pharmaceutiques (Médecine)info:eu-repo/semantics/nonPublishe

Uncovering TNBC molecular heterogeneity by applying integrative omics analyses with potential clinical implications

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The core spliceosomal factor U2AF1 controls cell-fate determination via the modulation of transcriptional networks

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Identification of let-7a as a target to prevent chemotherapy-induced ovarian damage in mouse model: a novel & non-invasive pharmacological approach in future fertility preservation strategies

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Let-7a as a target to prevent chemotherapy-induced ovarian damage in mouse model: a novel & non-invasive pharmacological approach in future fertility preservation strategies.

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Identification of let-7a as a target to prevent chemotherapy-induced ovarian damage in mouse model: a novel & non-invasive pharmacological approach in future fertility preservation strategies: Flash oral presentation

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