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Tumor-derived prostaglandin E2 (PGE2) impairs antitumor immunity by priming suppressive functions on various immune cell types, including dendritic cells (DCs). In this way, tumors mediate DC dysfunction and hamper their antitumoral activity. PGE2 is known to modulate DC function via signaling through the E-type prostanoid receptor 2 (EP2) and EP4. Preclinical studies have demonstrated the therapeutic value of targeting EP2/4 receptor signaling in DCs. Ongoing phase 1 clinical trials with EP antagonists have shown immunomodulation in cancer patients. However, the systemic drug administration leads to off-target events and subsequent side effects. To limit the off-target effects of EP targeting, EP2 and EP4 antagonists were encapsulated in polymeric nanoparticles (NPs). In this study, we evaluated the efficacy of EP2/4-specific antagonists encapsulated in NPs to protect conventional type 2 DCs (cDC2s) from suppressive effects of tumor-derived PGE2 in different tumor models. We show that tumor-derived PGE2 signals via EP2/4 to mediate the acquisition of a suppressive phenotype of cDC2s. EP2/4 antagonists encapsulated in NPs impaired the conversion of cDC2s toward a suppressive state and inhibited the occurrence of suppressive features such as interleukin-10 production or the ability to expand regulatory T cells. Importantly, the NPs abolished the transition toward this suppressive state in different tumor models: melanoma-conditioned media, ascites fluid derived from ovarian cancer patients (2-dimensional), and upon coculture with colorectal cancer patient-derived organoids (3-dimensional). We propose that targeting the PGE2-EP2/4 axis using NPs can achieve immunomodulation in the immune system of cancer patients, alleviate tumor-derived suppression, and thus facilitate the development of potent antitumor immunity in cancer patients., Competing Interests: Conflict of interest statement. J.A.F. is an employee of Miltenyi Biotec B.V. & Co. KG., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

Adaptive immunity relies on dendritic cell (DC) migration to transport antigens from tissues to lymph nodes. Galectins, a family of β-galactoside-binding proteins, control cell membrane organisation, exerting crucial roles in multiple physiological processes. Here, we report a novel mechanism underlying cell polarity and uropod retraction. We demonstrate that galectin-9 regulates chemokine-driven and basal DC migration both in humans and mice, indicating a conserved function for this lectin. We identified the underlying mechanism, namely a deficiency in cell rear contractility mediated by galectin-9 interaction with CD44 that in turn regulates RhoA activity. Analysis of DC motility in the 3D tumour-microenvironment revealed galectin-9 is also required for DC infiltration. Moreover, exogenous galectin-9 rescued the motility of tumour-immunocompromised human blood DCs, validating the physiological relevance of galectin-9 in DC migration and underscoring its implications for DC-based immunotherapies. Our results identify galectin-9 as a necessary mechanistic component for DC motility and highlight a novel role for the lectin in regulating cell polarity and contractility.

Metastatic colorectal cancer (CRC) is highly resistant to therapy and prone to recur. The tumor-induced local and systemic immunosuppression allows cancer cells to evade immunosurveillance, facilitating their proliferation and dissemination. Dendritic cells (DCs) are required for the detection, processing, and presentation of tumor antigens, and subsequently for the activation of antigen-specific T cells to orchestrate an effective antitumor response. Notably, successful tumors have evolved mechanisms to disrupt and impair DC functions, underlining the key role of tumor-induced DC dysfunction in promoting tumor growth, metastasis initiation, and treatment resistance. Conventional DC type 2 (cDC2) are highly prevalent in tumors and have been shown to present high phenotypic and functional plasticity in response to tumor-released environmental cues. This plasticity reverberates on both the development of antitumor responses and on the efficacy of immunotherapies in cancer patients. Uncovering the processes, mechanisms, and mediators by which CRC shapes and disrupts cDC2 functions is crucial to restoring their full antitumor potential. In this study, we use our recently developed 3D DC-tumor co-culture system to investigate how patient-derived primary and metastatic CRC organoids modulate cDC2 phenotype and function. We first demonstrate that our collagen-based system displays extensive interaction between cDC2 and tumor organoids. Interestingly, we show that tumor-corrupted cDC2 shift toward a CD14+ population with defective expression of maturation markers, an intermediate phenotype positioned between cDC2 and monocytes, and impaired T-cell activating abilities. This phenotype aligns with the newly defined DC3 (CD14 + CD1c + CD163 + ) subset. Remarkably, a comparable population was found to be present in tumor lesions and enriched in the peripheral blood of metastatic CRC patients. Moreover, using EP2 and EP4 receptor antagonists and an anti-IL-6 neutralizing antibody, we determined that the observed phenotype shift is partially mediated by PGE2 and IL-6. Importantly, our system holds promise as a platform for testing therapies aimed at preventing or mitigating tumor-induced DC dysfunction. Overall, our study offers novel and relevant insights into cDC2 (dys)function in CRC that hold relevance for the design of therapeutic approaches., (© 2024 The Authors. European Journal of Immunology published by Wiley‐VCH GmbH.)