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Systemic delivery of a targeted synthetic immunostimulant transforms the immune landscape for effective tumor regression.
Systemic delivery of a targeted synthetic immunostimulant transforms the immune landscape for effective tumor regression. Cell chemical biology Miller, C. L., Sagiv-Barfi, I., Neuhöfer, P., Czerwinski, D. K., Artandi, S. E., Bertozzi, C. R., Levy, R., Cochran, J. R. 2021Abstract
Promoting immune activation within the tumor microenvironment (TME) is a promising therapeutic strategy to reverse tumor immunosuppression and elicit anti-tumor immunity. To enable tumor-localized immunotherapy following intravenous administration, we chemically conjugated a polyspecific integrin-binding peptide (PIP) to an immunostimulant (Toll-like receptor 9 [TLR9] agonist: CpG) to generate a tumor-targeted immunomodulatory agent, referred to as PIP-CpG. We demonstrate that systemic delivery of PIP-CpG induces tumor regression and enhances therapeutic efficacy compared with untargeted CpG in aggressive murine breast and pancreatic cancer models. Furthermore, PIP-CpG transforms the immune-suppressive TME dominated by myeloid-derived suppressor cells into a lymphocyte-rich TME infiltrated with activated CD8+ T cells, CD4+ T cells, and B cells. Finally, we show that T cells are required for therapeutic efficacy and that PIP-CpG treatment generates tumor-specific CD8+ T cells. These data demonstrate that conjugation to a synthetic tumor-targeted peptide can improve the efficacy of systemically administered immunostimulants and lead to durable anti-tumor immune responses.
View details for DOI 10.1016/j.chembiol.2021.10.012
View details for PubMedID 34774126