Wang et al. generated cGAMP-loaded STING-activating polymeric nanoparticles (Poly-STING) that induced a burst of, and then sustained STING signaling. In mouse models, intratumoral Poly-STING injection induced rejection of established and metastatic tumors, and memory to tumor rechallenge, which required cDC1 STING-IFN-I signaling and CD8+ T cells. Analyses of tumors from Poly-STING-treated WT and cDC1-deficient hosts led to the definition of a STING-cDC1 chemokine profile. This profile correlated with better survival in patients with melanoma and sarcoma. Neoadjuvant pembrolizumab (+/- chemotherapy) treatment of patients with NSCLC increased the STING-cDC1 profile.
Contributed by Paula Hochman
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 ( XCR1 (cre) STING (fl/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. ONE SENTENCE SUMMARY: A "shock-and-lock" nanoparticle agonist induces direct STING signaling in type 1 conventional dendritic cells to drive antitumor immunity with defined biomarkers.
Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12)
Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12)
