Faculty, Staff and Student Publications

Language

English

Publication Date

2-16-2024

Journal

Science Immunology

DOI

10.1126/sciimmunol.adj3945

PMID

38363830

PMCID

PMC11822965

PubMedCentral® Posted Date

2-13-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP (cGAMP) in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations including cancer cells with distinct cellular functions such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here using a polymeric STING-activating nanoparticle (PolySTING) with a “shock-and-lock” dual activation mechanism, we show type 1 conventional dendritic cell (cDC1) is essential for STING-mediated rejection of multiple established and metastatic murine tumors. STING status in the host but not in the cancer cells (Tmem173−/−) is important for antitumor efficacy. Specific depletion of cDC1 (Batf3−/−) or STING deficiency in cDC1 (XCR1creSTINGfl/fl) abolished PolySTING efficacy, whereas depletion of other myeloid cells had little effect. Adoptive transfer of wildtype cDC1 in Batf3−/− mice restored antitumor efficacy while transfer of cDC1 with STING or IRF3 deficiency failed to rescue. PolySTING induced a specific chemokine signature in wildtype but not Batf3−/− mice. Multiplexed immunohistochemistry analysis of STING-activating cDC1s in resected tumors correlates with patient survival while also showing increased expressions after neoadjuvant pembrolizumab therapy in non-small cell lung cancer patients. Therefore, we have defined that a subset of myeloid cells is essential for STING-mediated antitumor immunity with associated biomarkers for prognosis.

Keywords

Animals, Humans, Mice, Carcinoma, Non-Small-Cell Lung, Dendritic Cells, DNA, Interferon Type I, Lung Neoplasms, Nanoparticles, Immunotherapy, STING Protein, Antibodies, Monoclonal, Humanized

Published Open-Access

yes

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