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

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 anti-tumor 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.

Mastectomía contralateral profiláctica con reconstrucción inmediata en pacientes con cáncer de mama unilateral sin mutación germinal en BRCA1/2 / Prophylactic contralateral mastectomy with immediate reconstruction in patients with unilateral breast cancer without germline BRCA1/2 mutations

Introducción No existe un consenso sobre las indicaciones de mastectomía contralateral en pacientes diagnosticadas de cáncer de mama unilateral sin mutación germinal en BRCA1/2. Estudios previos han identificado algunos factores que pueden influir en la toma de la decisión dependientes del tumor, como el tamaño o histología, de la paciente, como la edad, y de la cirugía como la posibilidad de realizar una reconstrucción inmediata o la experiencia del cirujano.MétodosEstudio retrospectivo de una cohorte de 176 pacientes diagnosticadas de CM entre 2010 y 2016 a las que se les realizó cirugía mamaria. Se ha analizado la asociación de características del tumor y de la paciente con la toma de decisión de realizar mastectomía contralateral (MC) o no-MC. Asimismo, se han analizado los datos relacionados con la cirugía y la recurrencia por grupos mediante la curva de incidencia acumulada y el test de Gray.ResultadosEl número de MC se ha incrementado en nuestro centro. No hemos encontrado diferencias significativas en el desarrollo de complicaciones posquirúrgicas entre los 2 grupos de pacientes, pero sí en la estancia hospitalaria, siendo superior para MC. También hemos observado diferencias entre ambas cohortes en edad y tipo de tumor, siendo la MC más frecuente en aquellas pacientes más jóvenes y subtipo luminal A. Hemos hallado diferencias en la incidencia acumulada de recidiva entre ambos subgrupos (p=0,034).ConclusionesEn nuestra cohorte la MC se realiza más frecuentemente en pacientes más jóvenes y con cáncer de mama luminal A.(AU)

Introduction There is no consensus on the indications for contralateral mastectomy (CM) in patients diagnosed with unilateral breast cancer without germline BRCA1/2 mutations. Prior studies have identified some factors that could influence decision-making. These factors include tumoural size and histological type; patient-related factors, such as age; and surgical factors such as the possibility of immediate reconstruction and the surgeon's experience.MethodsRetrospective study of a cohort of 176 patients diagnosed with breast cancer between 2010 and 2016 who underwent breast surgery. We analysed the association between tumoural and patient-related characteristics with the decision to perform CM or not. We also analysed data related to surgery and recurrence by groups by using the cumulative incidence curve and the Gray test.ResultsThe number of CM has increased in our centre. We found no significant differences in the occurrence of post-surgical complications between the two patient groups but length of hospital stay was higher in CM. We also found differences between the two cohorts in age and tumoural type, with CM being more frequent in younger patients and those with luminal A subtype. Differences were found in the cumulative incidence of recurrence between subgroups (p=0.034).ConclusionsIn our cohort, CM was more frequent in younger patients and in those with luminal A breast cancer.(AU)

Elderly breast cancer patients treated with Nab-paclitaxel: Results in real clinical practice / Cáncer de mama en pacientes ancianas: experiencia con Nab-paclitaxel en la práctica clínica real

Objective Clinical trials have shown that Nab-paclitaxel is more effective than paclitaxel in the treatment of metastatic breast cancer (MBC). Although the incidence of cancer increases with age, elderly patients are under-represented in clinical trials and tend to receive suboptimal treatment to avoid toxicity. The main aim of our study was to compare progression-free survival (PFS) among patients older and younger than 65 years treated with Nab-paclitaxel in real-world clinical practice. A secondary aim was to assess overall survival (OS) as well as the response rate and toxicity. Methods and patients This single-centre study retrospectively analyzed a cohort of 60 patients with MBC treated with Nab-paclitaxel monotherapy in Hospital Clínico Lozano Blesa de Zaragoza. Results The median PFS was 5.92 months (3.62–11.2) in patients<65 years and was 5.06 months (4.31–12.4) in those ≥65 years (p=0.868). The median OS was 26.9 months (18.6–30.7) in patients < 65 years and was 20.3 months (11.4–33.6) in those ≥65 years (p=0.138). Conclusions Although patients in the cohort studied had a median age of 60.45 years, which is higher than the median age in most clinical trials, PFS and OS in conditions of real-world clinical practice were similar to previously published data. The results of the use of Nab-paclitaxel in patients older than 65 years are similar to those in younger patients, with no additional toxicity problems. The results of our study agree with those of other notable studies. (AU)

Objetivo En los ensayos clínicos se ha demostrado que el Nab-paclitaxel es más eficaz que el paclitaxel en el tratamiento del cáncer de mama metastásico (CMM). Aunque la incidencia del cáncer aumenta con la edad, los pacientes ancianos están infrarrepresentados en los ensayos clínicos, y tienden a recibir un tratamiento subóptimo para evitar toxicidades. El objetivo principal de nuestro estudio es comparar la supervivencia libre de progresión (SLP) entre las mayores y menores de 65 años tratadas con Nab-paclitaxel en la práctica clínica real. El objetivo secundario es evaluar la supervivencia global (SG), así como la tasa de respuestas y la toxicidad. Métodos y pacientes Se ha analizado de forma unicéntrica y retrospectiva, una cohorte de 60 pacientes con CMM tratadas con Nab-paclitaxel en monoterapia en el Hospital Clínico Lozano Blesa de Zaragoza. Resultados Mediana SLP<65 años: 5,92 meses (3,62-11,2) y ≥65 años, mediana: 5,06 meses (4,31-12,4) (p=0,868). Mediana de SG en <65 años: 26,9 meses (18,6-30,7) y ≥65 años: 20,3 meses (11,4-33,6) (p=0,138). Conclusiones Aunque las pacientes de la cohorte estudiada tienen una mediana de edad de 60,45 años, que es superior a la mediana de edad de la mayoría de los ensayos clínicos, la SLP y la SG en condiciones de práctica clínica real son similares a los datos publicados anteriormente. En cuanto al uso de Nab-paclitaxel en pacientes de edad avanzada, se obtienen resultados similares a las de aquellas pacientes más jóvenes, sin observarse problemas de seguridad adicionales. Además, con los datos disponibles, los resultados son congruentes con los presentados en otros estudios de impacto. (AU)

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.