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Tesis inédita presentada en la Universidad Europea de Madrid. Escuela de Doctorado e Investigación. Programa de Doctorado en Actividad Física y Deporte El objetivo de esta tesis fue evaluar los efectos de un programa de ejercicio físico a planificado en un modelo ortotópico murino de neurobiastoma de alto riesgo. Para ello, se utilizaron 35 ratones macho wild-type TH-MYCN que fueron asignados aleatoriamente en un grupo ejercicio (n=17) o un grupo sedentario (n=16) tras la inoculación ortotópica de las neuroesferas tumorales. Se realizó un programa de ejercicio físico planificado combinado de entrenamiento aeróbico y de fuerza durante 5 semanas. Se evaluaron la evolución clínica de la enfermedad y la supervivencia diariamente, así como diferentes variables relacionadas con la capacidad física y la fuerza muscular antes y después de la intervención con ejercicio. El volumen y el peso tumoral, la metástasis y las distintas mediciones en el microambiente tumoral se evaluaron únicamente al final de la intervención. Se observó que el grupo ejercicio mantuvo una mayor capacidad aeróbica desde el comienzo hasta el final de la intervención, sufriendo el grupo sedentario un mayor declive en la misma (ps0,05). Dentro del tumor, el grupo ejercicio mostró mayores niveles de expresión de caspasa 3 y del receptor 2 del factor de crecimiento endotelial vascular (ps0,05). En la sangre periférica, se encontraron diferencias significativas en el receptor 4-IBB de los linfocitos CD8+ (ps0,05), estando aumentado considerablemente en el grupo ejercicio. En conclusión, la realización de un programa de ejercicio físico en un modelo murino de neuroblastoma de alto riesgo se considera una intervención segura que produce mejoras notables en el ratón, aportando nuevas evidencias científicas que validan la futura utilización de programas de ejercicio físico en ambientes intrahospitalarios con pacientes de cáncer pediátrico. Our purpose was to evaluate the effects of a physical exercise program in a murine model of high-risk neuroblastoma. Thirty-five wild-type TH-MYCN male mice were allocated in one of two groups (exercise, n=17; sedentary, n=16) after orthotopic inoculation of high-risk neurobiastoma tumor cells. The exercise intervention lasted five weeks and included aerobic and strength exercises. Clinical evolution and survival were assessed daily in all the mice, and aerobic capacity and muscle strength were analyzed before and after the exercise intervention. In turn, tumor volume and weight, metastasis and different measures related to the tumoral microenvironment were assessed at the end of the intervention period. The maximal aerobic capacity in the sedentary group decreased significantly (pSO.05) during the study period, whereas it remained unchanged in the exercise group. As for intratumoral variables, the exercise group showed greater levels of caspase 3 and vascular endothelial growth factor receptor 2 expression (psO.05). There were also significant differences in peripheral blood 4-1BB CD8+ receptors (pS0.05), with the sedentary group showing a more marked decrease of these receptors throughout the study compared with the exercise group. In conclusion, a supervised exercise program intervention in a high-risk neuroblastoma murine model is safe and can induce some significant benefits, providing new scientific evidence that validates the future use of intrahospital physical exercise programs. No data 2021 UEM

Background: Lung cancer has the highest incidence and mortality rate in the world. One of the most promising new cancer therapies in recent years is immunotherapy, which is based on the blockade of immune checkpoints such as programmed cell death protein 1 (PD-1). Exercise training is beneficial to maintain and improve the quality of life of cancer patients, and it might also modulate the anti-tumoral efficiency of some chemotherapeutic agents. However, the potential of exercise combined with immunotherapy as a cancer therapy remains to be elucidated. Here, we examined the effects of exercise on tumor growth and its possible adjuvant effects when combined with anti-PD-1 immunotherapy (nivolumab) in a patient derived xenograft (PDX) model of non-small-cell lung carcinoma (NSCLC). Methods: We generated a PDX model using NOD-SCID gamma mice with subcutaneous grafts from tumor tissue of a patient with NSCLC. Animals were randomly assigned to one of four groups: non-exercise + isotype control (n=5), exercise + isotype control (n=5), non-exercise + nivolumab (n=6) or exercise + nivolumab (n=6). The animals undertook an 8- week moderate-intensity training regimen (treadmill aerobic exercise and strength training). Immunotherapy (nivolumab) or an isotype control was administered 2 days/week, for 6 weeks. Several tumor growth and microenvironment parameters were measured after the intervention. Results: Improvements in aerobic capacity and muscle strength (p=0.027 and p=0.005) were noted in exercised animals. Exercise alone reduced the tumor growth rate with respect to non-exercised mice (p=0.050). The double intervention (exercise + nivolumab) increased tumor necrosis and reduced apoptosis with respect to controls (p=0.026; p=0.030). All interventions achieved a reduction in proliferation compared with the control group (p=0.015, p=0.011, and p=0.011). Exercise alone increased myeloid tumor infiltrates (mostly neutrophils) with respect to the nivolumab only group (p=0.018). Finally, Vegf-a expression was higher in the nivolumab groups (in combination or not with exercise) than in exercise + isotype control group (p=0.045 and p=0.047, respectively). No other significant effects were found. Conclusions: Our results would suggest that aerobic and strength training should be studied as an adjuvant to cancer immunotherapy treatment. Spanish Ministry of Economy and Competitiveness and Fondos FEDER - Fondo de Investigaciones Sanitarias (PI15/00558, PI18/00139 & PIE14/0064) 6.308 JCR (2020) Q1, 40/162 Inmunology 1.557 SJR (2020) Q1, 21/125 Sports Science No data IDR 2019 UEM