A Transcriptomic Immunologic Signature Predicts Favorable Outcome in Neoadjuvant Chemotherapy Treated Triple Negative Breast Tumors

© 2019 Pérez-Pena, Tibor Fekete, Páez, Baliu-Piqué, García-Saenz, García-Barberán, Manzano, Pérez-Segura, Esparis-Ogando, Pandiella, Gyorffy and Ocaña.Limited therapeutic options exist for the treatment of patients with triple negative breast cancer (TNBC). Neoadjuvant chemotherapy is currently the standard of care treatment in the early stages of the disease, although reliable biomarkers of response have been scarcely described. In our study we explored whether immunologic signatures associated with inflamed tumors or hot tumors could predict the outcome to neoadjuvant chemotherapy. Publicly available transcriptomic data of more than 2,000 patients were evaluated. ROC plots were generated to assess the response to therapy. Cox proportional hazards regression was computed. Kaplan-Meier plots were drawn to visualize the survival differences. Higher expression of IDO1, CXCL9, CXCL10, HLA-DRA, HLA-E, STAT1, and GZMB were associated with a higher proportion without relapse in the first 5 y after chemotherapy in TNBC. The expression of these genes was associated with a high presence of CD8 T cells in responder patients using the EPIC bioinformatic tool. The strongest effect was observed for STAT1 (p = 1.8e-05 and AUC 0.69, p = 2.7e-06). The best gene-set signature to predict favorable RFS was the combination of IDO1, LAG3, STAT1, and GZMB (HR = 0.28, CI = 0.17–0.46, p = 9.8 E-08, FDR = 1%). However, no influence on pathological complete response (pCR) was observed. Similarly, no benefit was identified in any other tumor subtype: HER2 or estrogen receptor positive. In conclusion, we describe a set of immunologic genes that predict the outcome to neoadjuvant chemotherapy in TNBC, but not pCR, suggesting that this non-time to event endpoint is not a good surrogate marker to detect the long term outcome for immune activated tumors.This work was supported by the Instituto de Salud Carlos III (PI16/01121), ACEPAIN; Diputación de Albacete, CIBERONC and the CRIS Cancer Foundation (to AO). The Ministry of Economy and Competitiveness of Spain (BFU2015-71371-R), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and CIBERONC, the scientific foundation of the AECC and the CRIS Foundation (to AP). The work carried out in our laboratories received support from the European Community through the regional development funding program (FEDER). BG was supported by the NVKP_16-1-2016-0037, 2018-1.3.1-VKE-2018-00032, and KH-129581 grants

Transcriptomic Correlates of Immunologic Activation in Head and Neck and Cervical Cancer

© 2021 Saiz-Ladera, Baliu-Piqué, Cimas, Manzano, García-Barberán, Camarero, Hinojal, Pandiella, Győrffy, Stewart, Cruz-Hernández, Pérez-Segura and Ocana.Targeting the immune system has emerged as an effective therapeutic strategy for the treatment of various tumor types, including Head and Neck Squamous Cell Carcinoma (HNSCC) and Non-small-Cell Lung Cancer (NSCLC), and checkpoint inhibitors have shown to improve patient survival in these tumor types. Unfortunately, not all cancers respond to these agents, making it necessary to identify responsive tumors. Several biomarkers of response have been described and clinically tested. As of yet what seems to be clear is that a pre-activation state of the immune system is necessary for these agents to be efficient. In this study, using established transcriptomic signatures, we identified a group of gene combination associated with favorable outcome in HNSCC linked to a higher presence of immune effector cells. CD2, CD3D, CD3E, and CXCR6 combined gene expression is associated with improved outcome of HNSCC patients and an increase of infiltrating immune effector cells. This new signature also identifies a subset of cervical squamous cell carcinoma (CSCC) patients with favorable prognosis, who show an increased presence of immune effector cells in the tumor, which outcome shows similarities with the HP-positive HNSCC cohort of patients. In addition, CD2, CD3D, CD3E, and CXCR6 signature is able to predict the best favorable prognosis in terms of overall survival of CSSC patients. Of note, these findings were not reproduced in other squamous cell carcinomas like esophageal SCC or lung SCC. Prospective confirmatory studies should be employed to validate these findings.This work has been supported by Instituto de Salud Carlos III (PI16/01121 and PI19/00808), ACEPAIN; Diputación de Albacete, CIBERONC and CRIS Cancer Foundation (to AO). Ministry of Economy and Competitiveness of Spain (BFU2015-71371-R), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and CIBERONC, the scientific foundation of the AECC and the CRIS Foundation (to AP). The work carried out in our laboratories receive support from the European Community through the regional development funding program (FEDER)

Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer

© 2021 by the authors.The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis and drug resistance, particularly through their interplay with estrogen receptor signaling and DNA repair. Herein we explored genomic alterations in these processes using RNA-seq and mutation data from TCGA and METABRIC datasets, and analyzed them using a bioinformatic pipeline in search of those with prognostic and predictive capability which could qualify as subjects of drug research. Amplification of UBE2T, UBE2C, and BIRC5 conferred a worse prognosis in luminal A/B and basal-like tumors, luminal A/B tumors, and luminal A tumors, respectively. Higher UBE2T expression levels were predictive of a lower rate of pathological complete response in triple negative breast cancer patients following neoadjuvant chemotherapy, whereas UBE2C and BIRC5 expression was higher in luminal A patients with tumor relapse within 5 years of endocrine therapy or chemotherapy. The transcriptomic signatures of USP9X and USP7 gene mutations also conferred worse prognosis in luminal A, HER2-enriched, and basal-like tumors, and in luminal A tumors, respectively. In conclusion, we identified and characterized the clinical value of a group of genomic alterations in ubiquitination, SUMOylation, and neddylation enzymes, with potential for drug development in breast cancer.Work in Alberto Ocaña’s lab is supported by the Instituto de Salud Carlos III (ISCIII, PI19/00808); ACEPAIN; Diputación de Albacete; and the CRIS Cancer Foundation. Work in Atanasio Pandiella’s lab is supported by the Ministry of Economy and Competitiveness of Spain (BFU2015- 71371-R, the Junta de Castilla y León (CSI146P20), and the CRIS Foundation. Balázs Györffy is financed by the 2018-2.1.17-TET-KR-00001 grant and by the Higher Education Institutional Excellence Programme of the Ministry for Innovation and Technology (MIT) in Hungary, within the framework of the Bionic thematic programme of the Semmelweis University

Breast Cancer Heterogeneity and Response to Novel Therapeutics

© 2020 by the authors.Targeted cancer therapies against oncogenic drivers are actively being developed and tested in clinical trials. Targeting an oncogenic driver may only prove effective if the mutation is present in most tumoral cells. Therefore, highly heterogeneous tumors may be refractory to these therapies. This makes tumor heterogeneity a major challenge in cancer therapy. Although heterogeneity has traditionally been attributed to genetic diversity within cancer cell populations, it is now widely recognized that human cancers are heterogeneous in almost all distinguishable phenotypic characteristics. Understanding the genetic variability and also the non-genetic influences of tumor heterogeneity will provide novel insights into how to reverse therapeutic resistance and improve cancer therapy.This work has been supported by CRIS Cancer Foundation, Instituto de Salud Carlos III (PI19/00808), ACEPAIN, ALMOM, Diputación de Albacete and CIBERONC

In vivo deuterium labelling in mice supports a dynamic model for memory T-cell maintenance in the bone marrow

The maintenance and dynamics of memory T-cells in the bone marrow are a matter of ongoing debate. It has been suggested that memory T-cells in the bone marrow are maintained as long-lived, quiescent cells. We have recently shown that memory T-cells isolated from goat bone marrow undergo self-renewal and recirculate via the blood and lymph. Using the well-established memory T-cell markers CD44 and CD62L we here show very similar results in mice. This provides further support for the concept that memory T-cells are continuously self-renewing and recirculating between blood, bone marrow, spleen and lymph nodes

Adoptive Cell Therapy in Breast Cancer: A Current Perspective of Next-Generation Medicine

© 2020 Fuentes-Antrás, Guevara-Hoyer, Baliu-Piqué, García-Sáenz, Pérez-Segura, Pandiella and Ocaña.Immunotherapy has become a cornerstone in the treatment of cancer and changed the way clinicians and researchers approach tumor vulnerabilities. Durable responses are commonly observed with immune checkpoint inhibitors in highly immunogenic tumors, while the infusion of T cells genetically engineered to express chimeric antigen receptors (CARs) has shown impressive efficacy in certain types of blood cancer. Nevertheless, harnessing our own immunity has not proved successful for most breast cancer patients. In the era of genomic medicine, cellular immunotherapies may provide a more personalized and dynamic tool against tumors displaying heterogeneous mutational landscapes and antigenic pools. This approach encompasses multiple strategies including the adoptive transfer of tumor-infiltrating lymphocytes, dendritic cells, natural killer cells, and engineered immune components such as CAR constructs and engineered T cell receptors. Although far from permeating the clinical setting, technical advances have been overwhelming in recent years, with continuous improvement in traditional challenges such as toxicity, adoptive cell persistence, and intratumoral trafficking. Also, there is an avid search for neoantigens that can be targeted by these strategies, either alone or in combination. In this work, we aim to provide a clinically-oriented overview of preclinical and clinical data regarding the use of cellular immunotherapies in breast cancer

Age-related distribution and dynamics of T-cells in blood and lymphoid tissues of goats

Neonatal mammals have increased disease susceptibility and sub-optimal vaccine responses. This raises problems in both humans and farm animals. The high prevalence of paratuberculosis in goats and the lack of an effective vaccine against it have a strong impact on the dairy sector, and calls for vaccines optimized for the neonatal immune system. We characterized the composition of the T-cell pool in neonatal kids and adult goats and quantified their turnover rates using in vivo deuterium labelling. From birth to adulthood, CD4+ T-cells were the predominant subset in the thymus and lymph nodes, while spleen and bone marrow contained mainly CD8+ lymphocytes. In blood, CD4+ T-cells were the predominant subset during the neonatal period, while CD8+ T-cells predominated in adults. We observed that thymic mass and cellularity increased during the first 5 months after birth, but decreased later in life. Deuterium labelling revealed that T-cell turnover rates in neonatal kids are considerably higher than in adult animals

Age-related distribution and dynamics of T-cells in blood and lymphoid tissues of goats

Neonatal mammals have increased disease susceptibility and sub-optimal vaccine responses. This raises problems in both humans and farm animals. The high prevalence of paratuberculosis in goats and the lack of an effective vaccine against it have a strong impact on the dairy sector, and calls for vaccines optimized for the neonatal immune system. We characterized the composition of the T-cell pool in neonatal kids and adult goats and quantified their turnover rates using in vivo deuterium labelling. From birth to adulthood, CD4+ T-cells were the predominant subset in the thymus and lymph nodes, while spleen and bone marrow contained mainly CD8+ lymphocytes. In blood, CD4+ T-cells were the predominant subset during the neonatal period, while CD8+ T-cells predominated in adults. We observed that thymic mass and cellularity increased during the first 5 months after birth, but decreased later in life. Deuterium labelling revealed that T-cell turnover rates in neonatal kids are considerably higher than in adult animals

Age-related distribution and dynamics of T-cells in blood and lymphoid tissues of goats

Neonatal mammals have increased disease susceptibility and sub-optimal vaccine responses. This raises problems in both humans and farm animals. The high prevalence of paratuberculosis in goats and the lack of an effective vaccine against it have a strong impact on the dairy sector, and calls for vaccines optimized for the neonatal immune system. We characterized the composition of the T-cell pool in neonatal kids and adult goats and quantified their turnover rates using in vivo deuterium labelling. From birth to adulthood, CD4+ T-cells were the predominant subset in the thymus and lymph nodes, while spleen and bone marrow contained mainly CD8+ lymphocytes. In blood, CD4+ T-cells were the predominant subset during the neonatal period, while CD8+ T-cells predominated in adults. We observed that thymic mass and cellularity increased during the first 5 months after birth, but decreased later in life. Deuterium labelling revealed that T-cell turnover rates in neonatal kids are considerably higher than in adult animals.</p

Age-related distribution and dynamics of T-cells in blood and lymphoid tissues of goats

Neonatal mammals have increased disease susceptibility and sub-optimal vaccine responses. This raises problems in both humans and farm animals. The high prevalence of paratuberculosis in goats and the lack of an effective vaccine against it have a strong impact on the dairy sector, and calls for vaccines optimized for the neonatal immune system. We characterized the composition of the T-cell pool in neonatal kids and adult goats and quantified their turnover rates using in vivo deuterium labelling. From birth to adulthood, CD4+ T-cells were the predominant subset in the thymus and lymph nodes, while spleen and bone marrow contained mainly CD8+ lymphocytes. In blood, CD4+ T-cells were the predominant subset during the neonatal period, while CD8+ T-cells predominated in adults. We observed that thymic mass and cellularity increased during the first 5 months after birth, but decreased later in life. Deuterium labelling revealed that T-cell turnover rates in neonatal kids are considerably higher than in adult animals