Generation of tumor-specific T cells is critically important for cancer immunotherapy1,2. A major challenge in achieving a robust T cell response is the spatio-temporal orchestration of antigen cross-presentation in antigen presenting cells (APCs) with innate stimulation. Here we report a minimalist nanovaccine by a simple physical mixture of an antigen with a synthetic polymeric nanoparticle, PC7A NP, which generated a strong cytotoxic T cell response with low systemic cytokine expression. Mechanistically, PC7A NP achieved efficient cytosolic delivery of tumor antigens to APCs in draining lymph nodes leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes. This effect was dependent on STING but not Toll-like receptor or MAVS pathway. Nanovaccine produced potent tumor growth inhibition in melanoma, colon cancer, and human papilloma virus-E6/E7 tumor models. Combination of PC7A nanovaccine with an anti-PD-1 antibody showed great synergy with 100% survival over 60 days in a TC-1 tumor model. Rechallenging of these tumor-free animals with TC-1 cells led to complete inhibition of tumor growth, suggesting generation of long-term antitumor memory. The STING-activating nanovaccine offers a simple, safe and robust strategy in boosting anti-tumor immunity for cancer immunotherapy.

Secreted frizzled related proteins (sFRPs) have emerged as key regulators of a wide range of developmental and disease processes, with virtually all known functions of mammalian sFRPs attributed to their ability to antagonize Wnt signaling. Recently however, the Xenopus and zebrafish sFRP, Sizzled, was shown to function as an antagonist of Chordin processing by Tolloid-like metalloproteinases, leading to the proposal that sFRPs may function as evolutionarily-conserved antagonists of the chordinase activities of this class of proteinases. Herein, in contrast to this proposal, we show that the mammalian sFRP, sFRP2, does not affect Chordin processing, but instead can serve as a direct enhancer of the procollagen C-proteinase activity of Tolloid-like metalloproteinases. We further show that the level of fibrosis, in which procollagen processing by Tolloid-like proteinases plays a rate-limiting role, is markedly reduced in sFRP2-null mice subjected to myocardial infarction. Importantly, this reduced level of fibrosis is accompanied by significantly improved cardiac function. This study thus uncovers a novel function for sFRP2 and a potential therapeutic application for sFRP2 antagonism in controlling fibrosis in the infarcted heart.

Immunological tolerance of tumors is characterized by insufficient infiltration of cytotoxic T lymphocytes (CTLs) and immunosuppressive microenvironment of tumor. Tumor resistance to immune checkpoint inhibitors due to immunological tolerance is an ongoing challenge for current immune checkpoint blockade (ICB) therapy. Here, we report the development of tumor microenvironment–activatable anti-PDL1 antibody (αPDL1) nanoparticles for combination immunotherapy designed to overcome immunological tolerance of tumors. Combination of αPDL1 nanoparticle treatment with near-infrared (NIR) laser irradiation–triggered activation of photosensitizer indocyanine green induces the generation of reactive oxygen species, which promotes the intratumoral infiltration of CTLs and sensitizes the tumors to PDL1 blockade therapy. We showed that the combination of antibody nanoparticles and NIR laser irradiation effectively suppressed tumor growth and metastasis to the lung and lymph nodes in mouse models. The nanoplatform that uses the antibody nanoparticle alone both for immune stimulation and PDL1 inhibition could be readily adapted to other immune checkpoint inhibitors for improved ICB therapy.

Pretreatment NLR and PLR can be independent prognostic factors for patients with NPC. © 2015 Wiley Periodicals, Head Neck 38: E1332-E1340, 2016.