Impacto del estudio genético de BRCA1 y BRCA2 en la decisión terapéutica en pacientes diagnosticadas de cáncer de mama triple negativo que reciben quimioterapia neoadyuvante

Este trabajo sobre la realización del estudio genético de los genes BRCA1 y BRCA2 en pacientes con cáncer de mama que reciben tratamiento neoadyuvante es de gran actualidad. Desde que en los años 90 se conoció la relación entre BRCA 1 y 2 y el síndrome de cáncer de mama y ovario hereditario los conocimientos sobre este síndrome se han visto ampliados de manera extraordinaria gracias en parte a los avances tecnológicos que se han incorporado y han permitido obtener los resultados de los estudios genéticos en un plazo de tiempo mucho menor. Cada vez más, la realización de estos estudios permite influir en el manejo clínico de pacientes diagnosticadas de cáncer y no ser sólo un instrumento para conocer la probabilidad de desarrollar cáncer en personas sanas. El cáncer de mama es el cáncer más frecuente en mujeres y la probabilidad de curación a 5 años supera el 80% en países desarrollados. Por ello, en estas pacientes tienen gran importancia las medidas de prevención terciaria. Este es un trabajo original que trata de evaluar en una cohorte de pacientes muy seleccionada por subtipo tumoral y tratamiento que reciben cómo los resultados de un test genético influyen en las decisiones sobre el tratamiento a los que se puede sumar medidas de prevención evitando segundas intervenciones para estas pacientes

Integración de agentes regionales de innovación y prestación de servicios avanzados de vigilancia tecnológica e inteligencia competitiva para PYMEs: el caso Zaintek

The phases and tools of the technological monitoring and competitive intelligence service (Zaintek) for the small and medium companies of Bizkaia (Spain) are presented. The development of this added value service is shown from its conception to its use by the firms. It is an initiative of the Department of Innovation and Economic Promotion of the Government of Vizcaya. The landmarks followed during the first year of its launching are explained, the performance indicators are presented, and some of the future actions are advanced. It constitutes an example of the dynamizing role that public administrations can have in sensibilizing the companies to the need of incorporating strategic intelligence as a tool for supporting the processes of decision makingSe presentan las diferentes fases y herramientas de desarrollo de un servicio de vigilancia tecnológica e inteligencia competitiva (Zaintek) para pequeñas y medianas empresas (PYME) de Vizcaya, desde su concepción hasta su utilización por las empresas, como servicio de valor añadido. Se trata de una iniciativa del Departamento de Innovación y Promoción Económica de la Diputación Foral de Vizcaya. Se muestran las hitos desarrollados durante el año de lanzamiento, los indicadores de resultados obtenidos, y el avance de alguna de las acciones de futuro. Constituye un ejemplo del papel dinamizador de la Administración en la sensibilización de las PYMEs para que incorporen la información estratégica como herramienta de apoyo en la toma de decisiones. (Autor

PD-1 is expressed in cytotoxic granules of NK cells and rapidly mobilized to the cell membrane following recognition of tumor cells

5 figures.-- Supplementary information available.The contribution of the T cell-related inhibitory checkpoint PD-1 to the regulation of NK cell activity is still not clear with contradictory results concerning its expression and role in the modulation of NK cell cytotoxicity. We provide novel key findings on the mechanism involved in the regulation of PD-1 expression on NK cell membrane and its functional consequences for the elimination of cancer cells. In contrast to freshly isolated NK cells from cancer patients, those from healthy donors did not express PD-1 on the cell membrane. However, when healthy NK cells were incubated with tumor target cells, membrane PD-1 expression increased, concurrent with the CD107a surface mobilization. This finding suggested that PD-1 was translocated to the cell membrane during NK cell degranulation after contact with target cells. Indeed, cytosolic PD-1 was expressed in freshly-isolated-NK cells and partly co-localized with CD107a and GzmB, confirming that membrane PD-1 corresponded to a pool of preformed PD-1. Moreover, NK cells that had mobilized PD-1 to the cell membrane presented a significantly reduced antitumor activity on PD-L1-expressing-tumor cells in vitro and in vivo, which was partly reversed by using anti-PD-1 blocking antibodies. Our results indicate that NK cells from healthy individuals express cytotoxic granule-associated PD-1, which is rapidly mobilized to the cell membrane after interaction with tumor target cells. This novel finding helps to understand how PD-1 expression is regulated on NK cell membrane and the functional consequences of this expression during the elimination of tumor cells, which will help to design more efficient NK cell-based cancer immunotherapies.Work in the JP laboratory is funded by FEDER (Fondo Europeo de Desarrollo Regional), Gobierno de Aragón (Group B29_20R), Ministerio de Ciencia, Innovación y Universidades (MCUN), Agencia Estatal de Investigación (SAF2017-83120-C2-1-R; PID2020-113963RBI00), Fundación Inocente Inocente, ASPANOA, and Carrera de la Mujer de Monzón. Postdoctoral Juan de la Cierva Contract (MA and LS) and Predoctoral Grant from AECC (CP). JP is supported by ARAID Foundation; Fundación Agencia Aragonesa para la investigación y el Desarrollo; Fundación Científica Asociación Española Contra el Cáncer.Peer reviewe

How could antibiotics, probiotics, and corticoids modify microbiota and its influence in cancer immune checkpoint inhibitors: a review

Immunotherapy has become a new paradigm in oncology, improving outcomes for several types of cancer. However, there are some aspects about its management that remain uncertain. One of the key points that needs better understanding is the interaction between immunotherapy and gut microbiome and how modulation of the microbiome might modify the efficacy of immunotherapy. Consequently, the negative impact of systemic antibiotics and corticosteroids on the efficacy of immunotherapy needs to be clarified.Peer reviewe

Intratumoral versus circulating lymphoid cells as predictive biomarkers in lung cancer patients treated with immune checkpoint inhibitors: Is the easiest path the best one?

This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities.The molecular and cell determinants that modulate immune checkpoint (ICI) efficacy in lung cancer are still not well understood. However, there is a necessity to select those patients that will most benefit from these new treatments. Recent studies suggest the presence and/or the relative balance of specific lymphoid cells in the tumor microenvironment (TEM) including the T cell (activated, memory, and regulatory) and NK cell (CD56dim/bright) subsets, and correlate with a better response to ICI. The analyses of these cell subsets in peripheral blood, as a more accessible and homogeneous sample, might facilitate clinical decisions concerning fast prediction of ICI efficacy. Despite recent studies suggesting that lymphoid circulating cells might correlate with ICI efficacy and toxicity, more analyses and investigation are required to confirm if circulating lymphoid cells are a relevant picture of the lung TME and could be instrumental as ICI response biomarkers. This short review is aimed to discuss the recent advances in this fast-growing field.J.P. reports research funding from BMS and Gilead and speaker honoraria from Gilead and Pfizer. E.M.G. reports research funding from BMS and Gilead. J.P. and E.M.G. are funded by FEDER (Fondo Europeo de Desarrollo Regional, Gobierno de Aragón (Group B29_17R), Ministerio de Ciencia, Innovación e Universidades (MCNU), Agencia Estatal de Investigación (SAF2017-83120-C2-1-R), Fundacion Inocente Inocente, ASPANOA and Carrera de la Mujer de Monzón. J.P. is supported by ARAID Foundation

Microbiota and lung cancer. Opportunities and challenges for improving immunotherapy efficacy

The advances in molecular biology and the emergence of Next Generation Sequencing (NGS) have revealed that microbiome composition is closely related with health and disease, including cancer. This relationship affects different levels of cancer such as development, progression, and response to treatment including immunotherapy. The efficacy of immune checkpoint inhibitors (ICIs) may be influenced by the concomitant use of antibiotics before, during or shortly after treatment with ICIs. Nevertheless, the linking mechanism between microbiote, host immunity and cancer is not clear and the role of microbiota manipulation and analyses in cancer management has not been clinically validated yet. Regarding the use of microbiome as biomarker to predict ICI efficacy it has been recently shown that the use of biochemical serum markers to monitor intestinal permeability and loss of barrier integrity, like citrulline, could be useful to monitor microbiota changes and predict ICI efficacy. There are still many unknowns about the role of these components, their relationship with the microbiota, with the use of antibiotics and the response to immunotherapy. The next challenge in microbiome research will be to identify individual microbial species that causally affect lung cancer phenotypes and response to ICI and disentangle the underlying mechanisms. Thus, further analyses in patients with lung cancer receiving treatment with ICIs and its correlation with the composition of the microbiota in different organs including the respiratory tract, peripheral blood and intestinal tract could be useful to predict the efficacy of ICIs and its modulation with antibiotic use.JP reported research funding from BMS and Gilead and speaker honoraria from Gilead and Pfizer. EG reported research funding from BMS and Gilead. JP and EG were funded by FEDER (Fondo Europeo de Desarrollo Regional, Gobierno de Aragón (Group B29_17R), Ministerio de Ciencia, Innovación e Universidades (MCNU), Agencia Estatal de Investigación (SAF2017-83120-C2- 1-R), Fundacion Inocente Inocente, ASPANOA and Carrera de la Mujer de Monzón. JP was supported by ARAID Foundation. DI reported consultation honoraria from AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche, Merck, MSD, Novartis, Pierre Fabre, Pfizer, and Takeda. DI reported speaker honoraria from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche, MSD, Novartis, Pierre Fabre, and Pfizer. DI reported research grant from AstraZeneca, BMS, F. Hoffmann-La Roche, MSD, and Pierre Fabre.Peer reviewe

From tumor mutational burden to blood T cell receptor: Looking for the best predictive biomarker in lung cancer treated with immunotherapy

2 tables.Immune control inhibitor drugs (anti-PD1/PD-L1/CTLA-4) (ICIs) are showing efficacy in the treatment of lung cancer. Currently the only biomarker with clinical utility for ICIs, such as the expression of PDL1, does not appear to be perfect or effective. Our working group is conducting a pilot study in lung cancer patients receiving ICIs with the aim of analyze the factors that affect the sensitivity of the immunotherapy in lung Cancer. Tumor Mutational Burden (TMB) and the sequencing of the T Cell Receptor (TCR) repertoire in peripheral blood have been postulated as predictive biomarkers of efficacy of immunotherapy. The review focusses on the predictive value of TMB for clinical responses to ICIs and discusses its clinical need after a discussion of the limitations. TCR CDR3 beta analysis and parameters such as clonality and TCR convergence may be good alternatives. For the moment, the combination of biomarkers may be the optimal tool.Despite therapeutic advances, lung cancer (LC) is one of the leading causes of cancer morbidity and mortality worldwide. Recently, the treatment of advanced LC has experienced important changes in survival benefit due to immune checkpoint inhibitors (ICIs). However, overall response rates (ORR) remain low in unselected patients and a large proportion of patients undergo disease progression in the first weeks of treatment. Therefore, there is a need of biomarkers to identify patients who will benefit from ICIs. The programmed cell death ligand 1 (PD-L1) expression has been the first biomarker developed. However, its use as a robust predictive biomarker has been limited due to the variability of techniques used, with different antibodies and thresholds. In this context, tumor mutational burden (TMB) has emerged as an additional powerful biomarker based on the observation of successful response to ICIs in solid tumors with high TMB. TMB can be defined as the total number of nonsynonymous mutations per DNA megabases being a mechanism generating neoantigens conditioning the tumor immunogenicity and response to ICIs. However, the latest data provide conflicting results regarding its role as a biomarker. Moreover, considering the results of the recent data, the use of peripheral blood T cell receptor (TCR) repertoire could be a new predictive biomarker. This review summarises recent findings describing the clinical utility of TMB and TCRβ (TCRB) and concludes that immune, neontigen, and checkpoint targeted variables are required in combination for accurately identifying patients who most likely will benefit of ICIs.Peer reviewe