The role of dendritic cells in tumor microenvironments and their uses as therapeutic targets

Kim, Chae Won; Kim, Kyun Do; Lee, Kyung-Mi

doi:10.5483/bmbrep.2021.54.1.224

Cited by 41 publications

(37 citation statements)

References 110 publications

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“…The IL-1β/CXCL1/neutrophil axis is documented to drive intestinal mucosal inflammation, activated by ligation of intestinal pattern recognition receptors, including toll-like receptors (TLRs) 31 . In the context of MBI, TLR4 activation is known to drive intestinal toxicity 32 , 33 , however targeting TLR4 directly is challenging due to emerging regulation of tumour response 34 – 37 . As such, we selected anakinra as our intervention to inhibit inflammatory mechanisms downstream of TLR4.…”

Section: Discussionmentioning

confidence: 99%

Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra

Wardill

Mooij

Ferreira

et al. 2022

Sci Rep

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High-dose chemotherapy causes intestinal inflammation and subsequent breakdown of the mucosal barrier, permitting translocation of enteric pathogens, clinically manifesting as fever. Antibiotics are mainstay for controlling these complications, however, they are increasingly recognized for their detrimental effects, including antimicrobial resistance and dysbiosis. Here, we show that mucosal barrier injury induced by the mucotoxic chemotherapeutic agent, high-dose melphalan (HDM), is characterized by hyper-active IL-1b/CXCL1/neutrophil signaling. Inhibition of this pathway with IL-1RA, anakinra, minimized the duration and intensity of mucosal barrier injury and accompanying clinical symptoms, including diarrhea, weight loss and fever in rats. 16S analysis of fecal microbiome demonstrated a more stable composition in rats receiving anakinra, with reduced pathogen expansion. In parallel, we report through Phase IIA investigation that anakinra is safe in stem cell transplant patients with multiple myeloma after HDM. Ramping-up anakinra (100–300 mg administered intravenously for 15 days) did not cause any adverse events or dose limiting toxicities, nor did it change time to neutrophil recovery. Our results reinforce that strengthening the mucosal barrier may be an effective supportive care strategy to mitigate local and systemic clinical consequences of HDM. We are now conducting a Phase IIB multicenter, placebo-controlled, double-blinded trial to assess clinical efficacy of anakinra (AFFECT-2).Trial registration: ClinicalTrials.gov identifier: NCT03233776.

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Section: Discussionmentioning

confidence: 99%

Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra

Wardill

Mooij

Ferreira

et al. 2022

Sci Rep

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“…Most notably, we observed that tumor tissues of MC38 colon carcinoma in IP6K1 KO mice showed very little CD11c + dendritic cell infiltrate. When dendritic cells sense and present tumor antigens, naive antigen-specific CD4 + and CD8 + T cells are activated, thereby mediating anti-tumor activities (Gardner et al 2020 ; Kim et al 2021 ). Therefore, reduced detection of total and CD8 + killer T cell population in the tumor tissue from IP6K1 KO mice appears the consequence of defective IP6K1 KO dendritic cells.…”

Section: Discussionmentioning

confidence: 99%

Deletion of IP6K1 in mice accelerates tumor growth by dysregulating the tumor-immune microenvironment

Lee

Park

Hong

et al. 2022

Animal Cells and Systems

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A family of inositol hexakisphosphate kinases (IP6Ks) catalyzes the production of inositol pyrophosphate IP 7 (5-diphosphoinositolpentakisphosphate) which is known to modulate various biological events such as cell growth. While targeting IP6K1 in various cancer cells has been well reported to control cancer cell motility and invasiveness, the role of host IP6K1 in tumor progression remains unknown. By using a syngeneic MC38 murine mouse colon carcinoma model, here we examined how host IP6K1 in the tumor microenvironment influences tumor growth. In IP6K1 knockout (KO) mice, the growth of MC38 tumor cells was markedly accelerated and host survival was significantly shortened compared with wild-type (WT). Our flow cytometric analysis revealed that tumors grown in IP6K1 KO mice had lower immune suppressive myeloid cells and M1 polarized macrophages. Notably, infiltration of both antigen-presenting dendritic cells and CD8 + cytotoxic T lymphocytes into the tumor tissues was remarkably abrogated in IP6K1 KO condition. These studies suggest that enhanced tumor growth in IP6K1 KO mice resulted from reduced anti-tumor immunity due to disturbed immune cell actions in the tumor microenvironment. In conclusion, we demonstrate that host IP6K1 acts as a tumor suppressor, most likely by fine-tuning diverse tumor-immune cell interactions, which might have implications for improving the host response against cancer progression.

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“…Dendritic cells (DCs) are major antigen-presenting cells in tumor immune microenvironment and exert anti-cancer activity ( 22 , 23 ). DCs are divided into two principal cell populations, including cDCs and plasmacytoid DCs ( 24 , 25 ). cDCs are subdivided into two subtypes, type 1 cDC (cDC1) and type 2 cDC (cDC2) ( 23 , 24 ).…”

Section: Discussionmentioning

confidence: 99%

“…DCs are divided into two principal cell populations, including cDCs and plasmacytoid DCs ( 24 , 25 ). cDCs are subdivided into two subtypes, type 1 cDC (cDC1) and type 2 cDC (cDC2) ( 23 , 24 ). Both cDC1 and cDC2 had antitumor activities.…”

Section: Discussionmentioning

confidence: 99%

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Identification and validation of tumor microenvironment-related prognostic biomarkers in breast cancer

Zhong¹,

Jia²,

Zhang³

et al. 2021

Transl Cancer Res TCR

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Background: Stromal cells and immune cells in tumor microenvironment (TME) have been reportedto have significant value in the diagnosis and prognosis of cancers. We aimed to identify key biomarkers predicting survival in the TME of breast cancer.Methods: Cell type enrichment analysis was performed to estimate cell scores using the xCell method with gene expression data from public database. Least absolute shrinkage and selection operator (LASSO) regression was used to identify key signature from the cell scores.Results: Totally, 50 cells in TME had different scores between 1,078 breast cancer tissues and 112 adjacent normal tissues. We identified a 4-cell signature predicting breast cancer survival, including myocytes, natural killer T cell (NKT), conventional dendritic cell (cDC) and sebocytes, which was validated in the test set. Further analysis showed that cDC score was a key signature predicting prognosis of breast cancer. cDC score was significantly associated with molecular classification and stage of breast cancer, as well as expression level of Ki67. Spearman's correlation analysis found that cDC score was inversely correlated with the expression level of HER2. High cDC score may predicate better pathological complete response rate. Mechanism analysis indicated high cDC score was associated with elevated immune activity; IL-2 was a key gene associated with high cDC score; and Breast cancer patients with high IL-2 expression had a longer survival time. Conclusions:In conclusion, cDC score was a key signature predicting prognosis for breast cancer. cDCs may exert antitumor effects by upregulating IL-2.

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The role of dendritic cells in tumor microenvironments and their uses as therapeutic targets

Cited by 41 publications

References 110 publications

Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra

Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra

Deletion of IP6K1 in mice accelerates tumor growth by dysregulating the tumor-immune microenvironment

Identification and validation of tumor microenvironment-related prognostic biomarkers in breast cancer

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