Natural Killer (NK) cells and cancer: nanotechnology-based new methods development for the enhancement of antitumor immunotherapy efficacy

Abstract

[EU]Jakina denez, NK (ingelesetik ¿natural killer¿) eta T zelulak interleukinekin estimulatzeak, hala nolahobetu egiten ditu haien funtzio efektiboak, minbiziaren erauzteko estrategia izanik. Tesi honetannanoformulazio baten (IONP@hIL15HIS) diseinua eta genesia aurkezten dugu, nanomaterialbiobateragarri, biodegradagarri eta trakzionagarri batean oinarritua, NK eta T zelulak in vitro aktibatzendituena, nanopartikularen gainazalean interleukin-15 (IL-15) egoteagatik. In vitro egindakoesperimentuetan ikusi da, IL-15 proteina NPren gainazalean inmobilizatzeak onurak ekarri ditzazkeelaNK eta T zelulen aktibazioari dagokionez. Horretaz gain, in vivo esperimentazioa ere egin zen emaitzekerakutsi zuten IONP A-hIL15HIS tratatutako saguek tumore hazkuntza geldoaren joera zutela. Oro har,tesi honen emaitzak lehen urrats bat dira IL-15 inmobilizatua NP-n, hau da, IONP@hIL15HIS,minbiziaren tratamendurako tresna terapeutiko berri gisa kontsideratzeko.

[EN]It is known that the stimulation of natural killer (NK) and T cells with different cytokines, such as interleukins, enhances their effector functions, which is a reliable strategy for cancer elimination. In this thesis, we present the design and generation of a nanoformulation (IONP@hIL15HIS), based on a biocompatible, biodegradable, and traceable nanomaterial, which activates NK and T cells in vitro, by the presence of interleukin-15 (IL-15) on the surface of the nanoparticle (NP). Importantly, the immobilization of IL-15 on the NP provided this cytokine with certain properties, highlighting, among others, a capacity to lessen the downregulation of homing receptors when T and NK cells are stimulated. Furthermore, two in vivo studies were carried out for two purposes: 1) to model an adoptive cell transfer therapy where IONP@hIL15HIS pre-stimulated human cells were infused in immunodeficient mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) and 2) to evaluate the antitumoral therapeutic effect of IONP@hIL15HIS compared to soluble administration of IL-15 in a melanoma C56BL/6 bearing mouse model. Results showed that mice treated with IONP@hIL15HIS have a tendency to slow tumor growth. Altogether, the results from this thesis are a first step to consider immobilized IL-15 on NPs, i.e. IONP@hIL15HIS, as a new therapeutic tool for cancer treatment..