The tumour microenvironment shapes dendritic cell plasticity in a human organotypic melanoma culture

Blasio, Stefania Di; Wigcheren, Glenn F. van; Becker, Anouk M. D.; Duffelen, Anne van; Gorris, Mark A.J.; Verrijp, Kiek; Stefanini, Irene; Bakker, Gert-Jan; Bloemendal, Martine; Halilović, Altuna; Vasaturo, Angela; Bakdash, Ghaith; Hato, Stanleyson V.; Wilt, Johannes H. W. de; Schalkwijk, Joost; Vries, I. Jolanda M. de; Textor, Johannes; Bogaard, Ellen H. van den; Tazzari, Marcella; Figdor, Carl G.

doi:10.1038/s41467-020-16583-0

Cited by 55 publications

(68 citation statements)

References 57 publications

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“…The tumor microenvironment (TME) has an undeniable influence on cancer progression by affecting tumor growth and on the ability of stromal and immune cells to orchestrate immune responses locally [ 1 ]. Hypoxia is a key component of the TME and a severe intratumoral hypoxia is associated with increased risk of mortality [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Enhances the Expression of RNASET2 in Human Monocyte-Derived Dendritic Cells: Role of PI3K/AKT Pathway

Monaci

Coppola

Giuntini

et al. 2021

IJMS

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Hypoxia is a key component of the tumor microenvironment (TME) and promotes not only tumor growth and metastasis, but also negatively affects infiltrating immune cells by impairing host immunity. Dendritic cells (DCs) are the most potent antigen-presenting cells and their biology is weakened in the TME in many ways, including the modulation of their viability. RNASET2 belongs to the T2 family of extracellular ribonucleases and, besides its nuclease activity, it exerts many additional functions. Indeed, RNASET2 is involved in several human pathologies, including cancer, and it is functionally relevant in the TME. RNASET2 functions are not restricted to cancer cells and its expression could be relevant also in other cell types which are important players in the TME, including DCs. Therefore, this study aimed to unravel the effect of hypoxia (2% O2) on the expression of RNASET2 in DCs. Here, we showed that hypoxia enhanced the expression and secretion of RNASET2 in human monocyte-derived DCs. This paralleled the HIF-1α accumulation and HIF-dependent and -independent signaling, which are associated with DCs’ survival/autophagy/apoptosis. RNASET2 expression, under hypoxia, was regulated by the PI3K/AKT pathway and was almost completely abolished by TLR4 ligand, LPS. Taken together, these results highlight how hypoxia- dependent and -independent pathways shape RNASET2 expression in DCs, with new perspectives on its implication for TME and, therefore, in anti-tumor immunity.

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Section: Introductionmentioning

confidence: 99%

Hypoxia Enhances the Expression of RNASET2 in Human Monocyte-Derived Dendritic Cells: Role of PI3K/AKT Pathway

Monaci

Coppola

Giuntini

et al. 2021

IJMS

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“…Interestingly, we found that TAM heterogeneity is lost when isolated and cultured ex vivo in 2D conditions, emphasizing the need for TME signals to maintain their identity. In recent years, 3D cultures in hydrogels, including collagen [ 55 , 56 ], have provided valuable tools to accelerate tumor studies and TME modeling [ 33 , 34 ]. In the present study, we developed a 3D collagen co-culture system to mimic the melanoma TME and investigate how interactions between melanoma cells, fibroblasts, and macrophages shape the early stages of macrophage immune activity leading to such complex phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Studying all these variables in dynamic in vivo environments can be challenging when trying to identify individual contributions to TME evolution. Recent studies have demonstrated that organotypic melanoma cultures outperform 2D assays when studying TME-imprinting mechanisms and closely resemble tumor growth as observed in human lesions while supporting cell survival and function [ 32 , 33 ]. The use of 3D cultures may accelerate the identification of predictive and/or prognostic markers and the development of effective combination therapies [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype

Pizzurro

Liu

Bridges

et al. 2021

Cancers

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Tumor immune response is shaped by the tumor microenvironment (TME), which often evolves to be immunosuppressive, promoting disease progression and metastasis. An important example is melanoma tumors, which display high numbers of tumor-associated macrophages (TAMs) that are immunosuppressive but also have the potential to restore anti-tumor activity. However, to therapeutically target TAMs, there is a need to understand the early events that shape their tumor-promoting profile. To address this, we built and optimized 3D in vitro co-culture systems, composed of a collagen-I matrix scaffolding murine bone-marrow-derived macrophages (BMDMs), YUMM1.7 melanoma cells, and fibroblasts to recreate the early melanoma TME and study how interactions with fibroblasts and tumor cells modulate macrophage immune activity. We monitored BMDM behavior and interactions through time-lapse imaging and characterized their activation and secretion. We found that stromal cells induced a rapid functional activation, with increased motility and response from BMDMs. Over the course of seven days, BMDMs acquired a phenotype and secretion profile that resembled melanoma TAMs in established tumors. Overall, the direct cell–cell interactions with the stromal components in a 3D environment shape BMDM transition to a TAM-like immunosuppressive state. Our systems will enable future studies of changes in macrophage–stromal cross-talk in the melanoma TME

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“…In most cases, even though many tumor antigen-speci c T cells are present in tumor tissues, the tumors continue to grow. One of the primary explanations for this phenomenon is that the tumor microenvironment lessens the antitumor immune responses the tumor-antigen-speci c T cells could have [25]. Some studies have demonstrated that tumor antigen-speci c T cells suppress tumor growth in HCC [26][27][28].…”

Section: Discussionmentioning

confidence: 99%

Combined Therapy with Dendritic Cell Loaded-Exosomes Supplemented with PD-1 Inhibition Have Superior Antitumor Effect in Hepatocellular Carcinoma

Shi

Wang

Zhang

et al. 2021

Preprint

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Background Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths and has low sensitivity to conventional therapies. Dendritic cell (DC) loaded tumor-exosomes (TEX) have shown antitumor effects in a murine HCC model. However, the combined antitumor efftcts of DC-TEX and programmed death protein 1 antibody (PD-1 Ab) at different time application has not been investigated. Methods In this study, ectopic, orthotopic, and diethylnitrosamine (DENA)-induced HCC models were established and treated with DC-TEX alone or in combination with PD-1 Ab at different time points. Meanwhile, we established an orthotopic HCC model in BALB/C nude mice and restore t cells. Results The results showed that along with the increased number of CD8+ T cells, the PD-1+CD8+ T-cell population was also significantly increased after DC-TEX injection. The number of CD8+ T cells peaked 72 h after DC-TEX injection, and the PD-1+CD8+ T cells also showed a similar result. Subsequently, the PD-1 Ab was applied in combination with DC-TEX at a series of time points (0, 24,72, 96, 120 or 168 h). Surprisingly, the combined treatment showed strong antitumor effects and this effect was most prominent when PD-1 Ab was administerd at 72 h. In vitro, PD-1 Ab also significantly reversed the proliferative ability of PD-1+CD8+ T cells at 72 h. The combined antitumor effects of PD-1 Ab and DC-TEX were mainly through their stimulation on CD8+T cells proliferation as well as repression for T cell exhaustion. Conclusion In conclusion, the combination of DC-TEX and PD-1 Ab significantly suppresses tumor growth in a murine HCC model and that the antitumor effect is affected by the timing of PD-1 Ab treatment.

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The tumour microenvironment shapes dendritic cell plasticity in a human organotypic melanoma culture

Cited by 55 publications

References 57 publications

Hypoxia Enhances the Expression of RNASET2 in Human Monocyte-Derived Dendritic Cells: Role of PI3K/AKT Pathway

Hypoxia Enhances the Expression of RNASET2 in Human Monocyte-Derived Dendritic Cells: Role of PI3K/AKT Pathway

3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype

Combined Therapy with Dendritic Cell Loaded-Exosomes Supplemented with PD-1 Inhibition Have Superior Antitumor Effect in Hepatocellular Carcinoma

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