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Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.

Intravital microscopy (IVM) allows spatial and temporal imaging of different cell types in intact live tissue microenvironments. IVM has played a critical role in understanding cancer biology, invasion, metastases, and drug development. One considerable impediment to the field is the inability to interrogate the tumor microenvironment and its communication cascades during disease progression and therapeutic interventions. Here, a new implantable perfusion window chamber (PWC) is described that allows high‐fidelity in vivo microscopy, local administration of stains and drugs, and longitudinal sampling of tumor interstitial fluid. This study shows that the new PWC design allows cyclic multiplexed imaging in vivo, imaging of drug action, and sampling of tumor‐shed materials. The PWC will be broadly useful as a novel perturbable in vivo system for deciphering biology in complex microenvironments. [ABSTRACT FROM AUTHOR]

The efficient activation of professional antigen‐presenting cells—such as dendritic cells (DC)—in tumors and lymph nodes is critical for the design of next‐generation cancer vaccines and may be able to provide anti‐tumor effects by itself through immune stimulation. The challenge is to stimulate these cells without causing excessive toxicity. It is hypothesized that a multi‐pronged combinatorial approach to DC stimulation would allow dose reductions of innate immune receptor‐stimulating TLR3 agonists while enhancing drug efficacy. Here, a hybrid lipid nanoparticle (LNP) platform is developed and tested for double‐stranded RNA (polyinosinic:polycytidylic acid for TLR3 agonism) and immune modulator (L‐CANDI) delivery. This study shows that the ≈120 nm hybrid nanoparticles‐in‐nanoparticles effectively eradicate tumors by themselves and generate long‐lasting, durable anti‐tumor immunity in mouse models. [ABSTRACT FROM AUTHOR]

Immune-checkpoint blockers can promote sustained clinical responses in a subset of cancer patients. Recent research has shown that a subpopulation of tumor-infiltrating dendritic cells functions as gatekeepers, sensitizing tumors to anti-PD-1 treatment via production of interleukin-12 (IL-12). Hypothesizing that myeloid cell-targeted nanomaterials could be used to deliver small-molecule IL-12 inducers, we performed high-content image-based screening to identify the most efficacious small-molecule compounds. Using one lead candidate, LCL161, we created a myeloid-targeted nanoformulation that induced IL-12 production in intratumoral myeloid cells in vivo , slowed tumor growth as a monotherapy, and had no significant systemic toxicity. These results pave the way for developing combination immunotherapeutics by harnessing IL-12 production for immunostimulation. • LCL161 activates IL-12 production in murine dendritic cells • LCL161 can be complexed to nanoparticles for delivery to the tumor microenvironment • LCL161 nanoparticles regress tumors and outperform a free drug control Koch et al. describe the development of LCL161 nanoparticles for cancer immunotherapy. These nanoparticles deliver the small-molecule drug LCL161 to intratumoral dendritic cells, where it stimulates production of IL-12. This therapeutic could greatly enhance the efficacy of current checkpoint inhibitors. [ABSTRACT FROM AUTHOR]