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After several decades, therapeutic cancer vaccines now show signs of efficacy and potential to help patients resistant to other standard-of-care immunotherapies, but they have yet to realize their full potential and expand the oncologic armamentarium. Here, we classify cancer vaccines by what is known of the included antigens, which tumors express those antigens and where the antigens colocalize with antigen-presenting cells, thus delineating predefined vaccines (shared or personalized) and anonymous vaccines (ex vivo or in situ). To expedite clinical development, we highlight the need for accurate immune monitoring of early trials to acknowledge failures and advance the most promising vaccines. Brody and colleagues discuss the current status and potential of cancer vaccines, highlighting challenges and opportunities to advance promising candidates to the clinic.

Constructs containing artificial microRNA target sites have the potential to improve a range of therapeutic strategies that are based on gene delivery or viruses. The same technology can be used for experimental purposes, in animal transgenics and to study the functions of microRNAs. New technologies are emerging that utilize artificial microRNA (miRNA) target sites to exploit or inhibit endogenous miRNA regulation. This approach has been used to improve cell-specific targeting for gene and stem cell therapy studies and for animal transgenics, and also to reduce the toxicity of oncolytic viruses and to attenuate viral vaccines. Artificial targets have also been used to sponge or decoy miRNAs as a way to study their functions. This article considers the benefits of this approach and design considerations for future studies.

Key Points The study of animals with global knockouts of genes encoding various cytokines, cytokine receptors and transcription factors has been crucial for understanding the development and homeostatic requirements of monocytes, macrophages and dendritic cells. Depletion models — such as those using clodronate liposomes or animals that express the diphtheria toxin receptor under the control of a myeloid cell-specific gene promoter — have allowed for inducible and more precise elimination of various mononuclear phagocyte populations. Crossing mice that express Cre recombinase under the control of myeloid cell-specific promoters with animals that have 'floxed' genes has been used to achieve cell-type specific deletion of a particular gene. Identifying myeloid promoters with improved specificity for particular mononuclear phagocyte populations will be crucial in order to more precisely dissect the different functions of particular populations. Molecular profiling of specific mononuclear phagocyte populations will help to identify more specific promoters and candidate genes to analyse functionally. The development of new humanized mouse models holds the promise of accelerating the study of the human mononuclear phagocyte compartment. Immunologists are making good progress in unravelling the intricacies of the mononuclear phagocyte system, and this is largely due to recent technological advances. This article describes the current tools that exist for studying the origins and functions of mononuclear phagocytes and discusses the future technologies that will enable further progress in the field. The mononuclear phagocyte system (MPS) comprises monocytes, macrophages and dendritic cells. Tissue phagocytes share several cell surface markers, phagocytic capability and myeloid classification; however, the factors that regulate the differentiation, homeostasis and function of macrophages and dendritic cells remain largely unknown. The purpose of this manuscript is to review the tools that are currently available and those that are under development to study the origin and function of mononuclear phagocytes.

Immunotherapies directly enhancing anti-tumor CD8 + T cell responses have yielded measurable but limited success, highlighting the need for alternatives. Anti-tumor T cell responses critically depend on antigen presenting dendritic cells (DC), and enhancing mobilization, antigen loading and activation of these cells represent an attractive possibility to potentiate T cell based therapies. Here we show that expansion of DCs by Flt3L administration impacts in situ vaccination with oncolytic Newcastle Disease Virus (NDV). Mechanistically, NDV activates DCs and sensitizes them to dying tumor cells through upregulation of dead-cell receptors and synergizes with Flt3L to promote anti-tumor CD8 + T cell cross-priming. In vivo, Flt3L-NDV in situ vaccination induces parallel amplification of virus- and tumor-specific T cells, including CD8 + T cells reactive to newly-described neoepitopes, promoting long-term tumor control. Cross-presenting conventional Type 1 DCs are indispensable for the anti-tumor, but not anti-viral, T cell response, and type I IFN-dependent CD4 + Th1 effector cells contribute to optimal anti-tumor immunity. These data demonstrate that mobilizing DCs to increase tumor antigen cross-presentation improves oncolytic virotherapy and that neoepitope-specific T cells can be induced without individualized, ex vivo manufactured vaccines. Strategies to advance T cell based immune therapies are mostly focusing on the improvement of CD8 T cell effector functions, such as cytotoxicity or recruitment to the tumor. Here authors show that by combining in situ vaccination with oncolytic Newcastle Disease Virus and Flt3L-driven dendritic cell expansion, the anti-tumor T cell response is amplified via increased antigen cross-presentation.

Two large-scale resources for studying microRNA function are presented: one is a library of fluorescent sensors with a corresponding assay for global profiling of microRNA activity in different cell types; the other is a decoy library for suppressing microRNA activity individually or in pooled loss-of-function screens. We introduce two large-scale resources for functional analysis of microRNA (miRNA): a decoy library for inhibiting miRNA function and a sensor library for monitoring microRNA activity. To take advantage of the sensor library, we developed a high-throughput assay called Sensor-seq to simultaneously quantify the activity of hundreds of miRNAs. Using this approach, we show that only the most abundant miRNAs in a cell mediate target suppression. Over 60% of detected miRNAs had no discernible activity, which indicated that the functional 'miRNome' of a cell is considerably smaller than currently inferred from profiling studies. Moreover, some highly expressed miRNAs exhibited relatively weak activity, which in some cases correlated with a high target-to-miRNA ratio or increased nuclear localization of the miRNA. Finally, we show that the miRNA decoy library can be used for pooled loss-of-function studies. These tools are valuable resources for studying miRNA biology and for miRNA-based therapeutics.

Ovarian cancer is a leading cause of cancer deaths among women. Effective targets to treat advanced epithelial ovarian cancer (EOC) and biomarkers to predict treatment response are still lacking because of the complexity of pathways involved in ovarian cancer progression. Here we show that miR-181a promotes TGF-β-mediated epithelial-to-mesenchymal transition via repression of its functional target, Smad7. miR-181a and phosphorylated Smad2 are enriched in recurrent compared with matched-primary ovarian tumours and their expression is associated with shorter time to recurrence and poor outcome in patients with EOC. Furthermore, ectopic expression of miR-181a results in increased cellular survival, migration, invasion, drug resistance and in vivo tumour burden and dissemination. In contrast, miR-181a inhibition via decoy vector suppression and Smad7 re-expression results in significant reversion of these phenotypes. Combined, our findings highlight an unappreciated role for miR-181a, Smad7, and the TGF-β signalling pathway in high-grade serous ovarian cancer. Ovarian cancer is often diagnosed at a late stage when metastasis has already occurred. In this study, Parikh et al. show that mir-181a is involved in mediating the epithelial-to-mesenchymal transition in ovarian cancer, leading to activation of the TGF-β signalling pathway and metastasis.

The effects of drugs on the immune system is predicted by a data integration method. Understanding how drugs affect the immune system has consequences for treating disease and minimizing unwanted side effects. Here we present an integrative computational approach for predicting interactions between drugs and immune cells in a system-wide manner. The approach matches gene sets between transcriptional signatures to determine their similarity. We apply the method to model the interactions between 1,309 drugs and 221 immune cell types and predict 69,995 interactions. The resulting immune-cell pharmacology map is used to predict how five drugs influence four immune cell types in humans and mice. To validate the predictions, we analyzed patient records and examined cell population changes from in vivo experiments. Our method offers a tool for screening thousands of interactions to identify relationships between drugs and the immune system.

Plasmacytoid dendritic cells produce copious amounts of type I interferon in response to viral infection. Brown and colleagues show that the homeostasis and function of these cells are regulated by the microRNA miR-126. miR-126 is a microRNA expressed predominately by endothelial cells and controls angiogenesis. We found miR-126 was required for the innate response to pathogen-associated nucleic acids and that miR-126-deficient mice had greater susceptibility to infection with pseudotyped HIV. Profiling of miRNA indicated that miR-126 had high and specific expression by plasmacytoid dendritic cells (pDCs). Moreover, miR-126 controlled the survival and function of pDCs and regulated the expression of genes encoding molecules involved in the innate response, including Tlr7 , Tlr9 and Nfkb1 , as well as Kdr , which encodes the growth factor receptor VEGFR2. Deletion of Kdr in DCs resulted in reduced production of type I interferon, which supports the proposal of a role for VEGFR2 in miR-126 regulation of pDCs. Our studies identify the miR-126–VEGFR2 axis as an important regulator of the innate response that operates through multiscale control of pDCs.

Lipid nanoparticle (LNP)-mRNA vaccines have demonstrated protective capability in combating SARS-CoV-2. Their extensive deployment across the global population leads to the broad presence of T-cell immunity against the SARS-CoV-2 spike protein, presenting an opportunity to harness this immunological response as a universal antigen target for cancer treatment. Herein, we design and synthesize a series of amino alcohol- or amino acid-derived ionizable lipids (AA lipids) and develop an LNP-RNA-based antigen presentation platform to redirect spike-specific T-cell immunity against cancer in mouse models. First, in a prime-boost regimen, AA2 LNP encapsulating spike mRNA elicit stronger T-cell immunity against the spike epitopes compared to FDA-approved LNPs (ALC-0315 and SM-102), highlighting the superior delivery efficiency of AA2 LNP. Next, AA15V LNP efficiently delivers self-amplifying RNAs (saRNAs) encoding spike epitope-loaded single-chain trimer (sSE-SCT) MHC I molecules into tumor tissues, thereby inducing the presentation of spike epitopes. Our results show that a single intratumoral ( i.t. ) treatment of AA15V LNP-sSE-SCTs suppresses tumor growth and extends the survival of B16F10 melanoma and A20 lymphoma tumor-bearing mice vaccinated with AA2 LNP-spike mRNA. Additionally, AA15V LNP-sSE-SCTs enable SE-SCT expression in ex vivo human glioblastoma and lung cancer samples, suggesting its potential in clinical translation. Immunoengineering-based cancer therapies have huge potential. Here the authors report on the lipid nanoparticle delivery, to cancer cells, of self-amplifying RNA encoding SARS-CoV-2 spike epitope-loaded MHC I molecules to take advantage of anti-SARS-CoV-2 immunity from a vaccinated population to treat cancer.