Tumor cell lysate-loaded immunostimulatory spherical nucleic acids as therapeutics for triple-negative breast cancer
Menée in vitro et à l'aide de modèles murins de cancer du sein triple négatif, cette étude met en évidence l'intérêt thérapeutique d'acides nucléiques sphériques chargés en lysats de cellules tumorales et comportant des oligonucléotides immunostimulants
In mouse models of triple-negative breast cancer, we show that the oxidation of tumor cells prior to lysate generation, coupled with their compartmentalization in the core of liposomal spherical nucleic acids (SNAs) comprised of adjuvant DNA, yields a powerful immunotherapeutic that significantly inhibits tumor growth, dramatically extends survival, and promotes a tumoricidal immune cell population within the tumor microenvironment. Specifically, this work points toward the importance of properly packaging and presenting the adjuvant and antigens such that biodistribution, dendritic cell activation, and therapeutic efficacy can be controlled.Highly heterogenous cancers, such as triple-negative breast cancer (TNBC), remain challenging immunotherapeutic targets. Herein, we describe the synthesis and evaluation of immunotherapeutic liposomal spherical nucleic acids (SNAs) for TNBC therapy. The SNAs comprise immunostimulatory oligonucleotides (CpG-1826) as adjuvants and encapsulate lysates derived from TNBC cell lines as antigens. The resulting nanostructures (Lys-SNAs) enhance the codelivery of adjuvant and antigen to immune cells when compared to simple mixtures of lysates with linear oligonucleotides both in vitro and in vivo, and reduce tumor growth relative to simple mixtures of lysate and CpG-1826 (Lys-Mix) in both Py230 and Py8119 orthotopic syngeneic mouse models of TNBC. Furthermore, oxidizing TNBC cells prior to lysis and incorporation into SNAs (OxLys-SNAs) significantly increases the activation of dendritic cells relative to their nonoxidized counterparts. When administered peritumorally in vivo in the EMT6 mouse mammary carcinoma model, OxLys-SNAs significantly increase the population of cytotoxic CD8+ T cells and simultaneously decrease the population of myeloid derived suppressor cells (MDSCs) within the tumor microenvironment, when compared with Lys-SNAs and simple mixtures of oxidized lysates with CpG-1826. Importantly, animals administered OxLys-SNAs exhibit significant antitumor activity and prolonged survival relative to all other treatment groups, and resist tumor rechallenge. Together, these results show that the way lysates are processed and packaged has a profound impact on their immunogenicity and therapeutic efficacy. Moreover, this work points toward the potential of oxidized tumor cell lysate-loaded SNAs as a potent class of immunotherapeutics for cancers lacking common therapeutic targets.