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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. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) shape adaptive immunity in response to environmental cues such as cytokines or lipid mediators, including prostaglandin E2 (PGE2). In cancer, tumors are known to establish an enriched PGE2 microenvironment. Tumor‐derived PGE2 primes regulatory features across immune cells, including DCs, facilitating tumor progression. PGE2 shapes DC function by providing signaling via its two so‐called E‐prostanoid receptors (EPs) EP2 and EP4. Although studies with monocyte‐derived DCs have shown the importance of PGE2 signaling, the role of PGE2‐EP2/EP4 on conventional DCs type 2 (cDC2s), is still poorly defined. In this study, we investigated the function of EP2 and EP4 using specific EP antagonists on human cDC2s. Our results show that EP2 and EP4 exhibit different functions in cDC2s, with EP4 modulating the upregulation of activation markers (CD80, CD86, CD83, MHC class II) and the production of IL‐10 and IL‐23. Furthermore, PGE2‐EP4 boosts CCR type 7‐based migration as well as a higher T‐cell expansion capacity, characterized by the enrichment of suppressive rather than pro‐inflammatory T‐cell populations. Our findings are relevant to further understanding the role of EP receptors in cDC2s, underscoring the benefit of targeting the PGE2‐EP2/4 axis for therapeutic purposes in diseases such as cancer. [ABSTRACT FROM AUTHOR]

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. Tumorderived 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 protumor 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 tumorderived 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 antitumor immunity. [ABSTRACT FROM AUTHOR]