Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 17543-17550 |
| Number of pages | 8 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 117 |
| Issue number | 30 |
| DOIs | |
| State | Published - Jul 28 2020 |
Funding
and funded by the Office of Naval Research through Grant N00014-15-1-0043. C.E.C. acknowledges support from the Eden and Steven Romick PostDoctoral Fellowship through the American Committee for the Weizmann Institute of Science. L.E.C. acknowledges support from Northwestern University’s Cancer Nanotechnology Training Program Award T32CA186897. Z.H. was supported, in part, by the Northwestern University Graduate School Cluster in Biotechnology, Systems, and Synthetic Biology, which is affiliated ACKNOWLEDGMENTS. Research reported in this publication was supported by the National Cancer Institute of the NIH under Awards U54CA199091 and R01CA208783. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. It was also supported by the Prostate Cancer Foundation and the Movember Foundation under Award 17CHAL08, the Lefkofsky Family Foundation, and the Vannevar Bush Faculty Fellowship program sponsored by the Basic Research Office of the Assistant Secretary of Defense for Research and Engineering with the Biotechnology Training Program. D.H. was supported by the Lynn Sage Foundation as Lynn Sage Scholar. The cryo-TEM experiment made use of the BioCryo facility of Northwestern University’s NUANCE Center, which has received support from the SHyNE Resource (NSF ECCS-1542205), the International Institute for Nanotechnology, and Northwestern’s Materials Research Science and Engineering Center program (NSF DMR-1720139).
Keywords
- Cancer immunotherapy
- Cancer vaccines
- Oxidized tumor lysates
- Spherical nucleic acids
ASJC Scopus subject areas
- General
