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Tumors educate their environment to prime the occurrence of suppressive cell subsets, which enable tumor evasion and favors tumor progression. Among these, there are the myeloid-derived suppressor cells (MDSCs), their presence being associated with the poor clinical outcome of cancer patients. Tumor-derived prostaglandin E2 (PGE2) is known to mediate MDSC differentiation and the acquisition of pro-tumor features. In myeloid cells, PGE2 signaling is mediated via E-prostanoid receptor type 2 (EP2) and EP4. Although the suppressive role of PGE2 is well established in MDSCs, the role of EP2/4 on human MDSCs or whether EP2/4 modulation can prevent MDSCs suppressive features upon exposure to tumor-derived PGE2 is poorly defined. In this study, using an in vitro model of human monocytic-MDSCs (M-MDSCs) we demonstrate that EP2 and EP4 signaling contribute to the induction of a pro-tumor phenotype and function on M-MDSCs. PGE2 signaling via EP2 and EP4 boosted M-MDSC ability to suppress T and NK cell responses. Combined EP2/4 blockade on M-MDSCs during PGE2 exposure prevented the occurrence of these suppressive features. Additionally, EP2/4 blockade attenuated the suppressive phenotype of M-MDSCs in a 3D coculture with colorectal cancer patient-derived organoids. Together, these results identify the role of tumor-derived PGE2 signaling via EP2 and EP4 in this human M-MDSC model, supporting the therapeutic value of targeting PGE2-EP2/4 axis in M-MDSCs to alleviate immunosuppression and facilitate the development of anti-tumor immunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cuenca-Escalona, Subtil, Garcia-Perez, Cambi, de Vries and Flórez-Grau.)

Current treatment for patients with non-small-cell lung cancer (NSCLC) is suboptimal since therapy is only effective in a minority of patients and does not always induce a long-lasting response. This highlights the importance of exploring new treatment options. The clinical success of immunotherapy relies on the ability of the immune system to mount an adequate anti-tumor response. The activation of cytotoxic T cells, the effector immune cells responsible for tumor cell killing, is of paramount importance for the immunotherapy success. These cytotoxic T cells are primarily instructed by dendritic cells (DCs). DCs are the most potent antigen-presenting cells (APCs) and are capable of orchestrating a strong anti-cancer immune response. DC function is often suppressed in NSCLC. Therefore, resurrection of DC function is an interesting approach to enhance anti-cancer immune response. Recent data from DC-based treatment studies has given rise to the impression that DC-based treatment cannot induce clinical benefit in NSCLC by itself. However, these are all early-phase studies that were mainly designed to study safety and were not powered to study clinical benefit. The fact that these studies do show that DC-based therapies were well-tolerated and could induce the desired immune responses, indicates that DC-based therapy is still a promising option. Especially combination with other treatment modalities might enhance immunological response and clinical outcome. In this review, we will identify the possibilities from current DC-based treatment trials that could open up new venues to improve future treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van der Hoorn, Flórez-Grau, van den Heuvel, de Vries and Piet.)

Immunotherapeutic approaches have revolutionized the treatment of several diseases such as cancer. The main goal of immunotherapy for cancer is to modulate the anti-tumor immune responses by favoring the recognition and destruction of tumor cells. Recently, a better understanding of the suppressive effect of the tumor microenvironment (TME) on immune cells, indicates that restoring the suppressive effect of the TME is crucial for an efficient immunotherapy. Natural killer (NK) cells and dendritic cells (DCs) are cell types that are currently administered to cancer patients. NK cells are used because of their ability to kill tumor cells directly via cytotoxic granzymes. DCs are employed to enhance anti-tumor T cell responses based on their ability to present antigens and induce tumor-antigen specific CD8 + T cell responses. In preclinical models, a particular DC subset, conventional type 1 DCs (cDC1s) is shown to be specialized in cross-presenting extracellular antigens to CD8 + T cells. This feature makes them a promising DC subset for cancer treatment. Within the TME, cDC1s show a bidirectional cross-talk with NK cells, resulting in a higher cDC1 recruitment, differentiation, and maturation as well as activation and stimulation of NK cells. Consequently, the presence of cDC1s and NK cells within the TME might be of utmost importance for the success of immunotherapy. In this review, we discuss the function of cDC1s and NK cells, their bidirectional cross-talk and potential strategies that could improve cancer immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bödder, Zahan, van Slooten, Schreibelt, de Vries and Flórez-Grau.)

The identification of activated T-lymphocytes restricted to myelin-derived immunogenic peptides in multiple sclerosis (MS) and aquaporin-4 water channel in neuromyelitis optica (NMO) in the blood of patients opened the possibility for developing highly selective and disease-specific therapeutic approaches. Antigen presenting cells and in particular dendritic cells (DCs) represent a strategy to inhibit pro-inflammatory T helper cells. DCs are located in peripheral and lymphoid tissues and are essential for homeostasis of T cell-dependent immune responses. The expression of a particular set of receptors involved in pathogen recognition confers to DCs the property to initiate immune responses. However, in the absence of danger signals different DC subsets have been revealed to induce active tolerance by inducing regulatory T cells, inhibiting pro-inflammatory T helper cells responses or both. Interestingly, several protocols to generate clinical-grade tolerogenic DC (Tol-DC) in vitro have been described, offering the possibility to restore the homeostasis to central nervous system-related antigens. In this review, we discuss about different DC subsets and their role in tolerance induction, the different protocols to generate Tol-DCs and preclinical studies in animal models as well as describe recent characterization of Tol-DCs for clinical application in autoimmune diseases and in particular in MS and NMO patients. In addition, we discuss the clinical trials ongoing based on Tol-DCs to treat different autoimmune diseases.