Dendritic cells (DCs) are leukocytes that are emerging as chief orchestrators of immune responses. The crucial task of DCs is the continuous surveillance of antigen-exposed sites throughout the body, and their unique responsibility is to decide whether to present sampled antigen in an immunogenic or tolerogenic way. Any misstep can either lead to a flawed immune defense or to allergy, even autoimmunity. It comes as no surprise that the lungs become increasingly the subject of DC-related investigations, as they represent a vast interface between the body and the outer world. This constitutes an enormous challenge for the immune system: “firing up” immune responses inappropriately could have devastating results for the fragile gas exchange structures. Evidence accumulates that DCs play a pivotal role in maintaining the delicate balance between tolerance and active immune response in our respiratory system. The exponentially growing body of DC-related publications is a big challenge. This article aims to provide researchers and clinicians with an up-to-date view on DC biology and its relevance to pulmonary medicine. A developing trend in the field of DCs is the shift from fundamental immunologic research toward exciting clinical insights and applications. For the pulmonary clinician, this heralds the dawn of promising therapies in various domains such as infections, allergy, and cancer.

Background: The need to accurately discriminate dendritic cells (DCs) and macrophages (Mphs) in mouse lungs is critical given important biological differences. However, a validated flow cytometry–based method is still lacking, resulting in much confusion between both cell types.Methods: Single‐cell suspensions freshly obtained from collagenase‐digested lung tissue were stained with a CD11c‐specific monoclonal antibody, detected using a PE‐Cy5 or APC‐conjugated secondary reagent. Cellular immunophenotype was simultaneously explored using a panel of PE‐conjugated markers. The FL1 or FITC‐detection channel was reserved for the assessment of autofluorescence.Results: CD11c‐bright cells were heterogeneous and displayed a bimodal distribution with regard to autofluorescence (AF). CD11c+/low‐AF cells were lineage‐negative and showed features compatible with myeloid DCs. This was confirmed by morphology, potent T‐cell stimulatory function in a mixed‐leukocyte reaction, surface expression of MHCII and costimulatory molecules, and further immunophenotypical criteria, including the expression of Mac‐1 and absence of CD8α. In contrast, CD11c+/high‐AF cells displayed the features of pulmonary Mphs, including typical Mph morphology, very weak induction of T‐cell proliferation, low to absent expression of MHCII and costimulatory molecules, and very low levels of Mac‐1 as well as F4/80. We also show that only CD11c+/high‐AF cells strongly expressed the macrophage marker MOMA‐2, while interestingly Mac‐3 was expressed at high levels by CD11c+/high‐AF and low‐AF alike.Conclusions: This study shows that the combination of CD11c‐expression and autofluorescence is necessary and sufficient to accurately separate DCs from macrophage subpopulations in mouse lungs.

More than many other fields in medicine, cancer vaccine development has been plagued by a wide gap between the massive amounts of highly encouraging preclinical data on one hand, and the disappointing clinical results on the other. It is clear now that traditional approaches from the infectious diseases' vaccine field cannot be borrowed as such to treat cancer. This review highlights some of the strategies developed to improve vaccine formulations for oncology, including research into more powerful or “smarter” adjuvants to elicit anti-tumoral cellular immune responses. As an illustration of the difficulties in translating smart preclinical strategies into real benefit for the cancer patient, the difficult road of vaccine development in lung cancer is given as example. Finally, an outline is provided of the combinatorial strategies that leverage the increasing knowledge on tumor-associated immune suppressive networks. Indeed, combining with drugs that target the dominant immunosuppressive pathway in a given tumor promises to unlock the true power of cancer vaccines and potentially offer long-term protection from disease relapse.

MRNA therapeutics have become the focus of molecular medicine research. Various mRNA applications have reached major milestones at high speed in the immuno-oncology field. This can be attributed to the knowledge that mRNA is one of nature’s core building blocks carrying important information and can be considered as a powerful vector for delivery of therapeutic proteins to the patient.For a long time, the major focus in the use of in vitro transcribed mRNA was on development of cancer vaccines, using mRNA encoding tumor antigens to modify dendritic cells ex vivo. However, the versatility of mRNA and its many advantages have paved the path beyond this application. In addition, due to smart design of both the structural properties of the mRNA molecule as well as pharmaceutical formulations that improve its in vivo stability and selective targeting, the therapeutic potential of mRNA can be considered as endless.As a consequence, many novel immunotherapeutic strategies focus on the use of mRNA beyond its use as the source of tumor antigens. This review aims to summarize the state-of-the-art on these applications and to provide a rationale for their clinical application.

Lung cancer remains the leading cause of cancer-related death worldwide. The advent of immune checkpoint inhibitors has led to a paradigm shift in the treatment of metastatic non-small cell and small cell lung cancer. However, despite prolonged overall survival, only a minority of the patients derive clinical benefit from these treatments suggesting that the full anti-tumoral potential of the immune system is not being harnessed yet. One way to overcome this problem is to combine immune checkpoint blockade with different strategies aimed at inducing or restoring cellular immunity in a tumor-specific, robust, and durable way. Owing to their unique capacity to initiate and regulate T cell responses, dendritic cells have been extensively explored as tools for immunotherapy in many tumors, including lung cancer. In this review, we provide an update on the nearly twenty years of experience with dendritic cell-based immunotherapy in lung cancer. We summarize the main results from the early phase trials and give an overview of the future perspectives within this field.