Melanoma‐derived conditioned media efficiently induce the differentiation of monocytes to macrophages that display a highly invasive gene signature

Wang, Tao; Ge, Yali; Xiao, Min; López-Coral, Alfonso; Azuma, Rikka; Somasundaram, Rajasekharan; Zhang, Gao; Wei, Zhi; Xu, Xiaowei; Rauscher, Frank J.; Herlyn, Meenhard; Kaufman, Russel E.

doi:10.1111/j.1755-148x.2012.01005.x

Cited by 61 publications

(71 citation statements)

References 51 publications

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“…In nature, there are some atypical macrophages that share some pathological features with Th2, and also they showed similar phenotypes with IL-4/IL-13-induced M2 macrophages, such as TAMs, which also are named as AAMs but do not possess all the features of AAMs (4,33,46,56,57). In our current research, we obtained a similar conclusion.…”

Section: Caspase-6-regulated Alternative Activation Of Macrophagessupporting

confidence: 78%

Identification of Caspase-6 as a New Regulator of Alternatively Activated Macrophages

Yao

Shi

Chen

et al. 2016

Journal of Biological Chemistry

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Alternatively activated macrophages (AAMs) play essential roles in the promotion of tissue remodeling, vasculogenesis, and tumor progression; however, the detailed mechanisms underlying the activation of AAMs remain largely unknown. Here, by using quantitative proteomic analysis, we identified 62 proteins that were up-regulated in IL-4-induced macrophages. Among these, Caspase-6 was increased significantly. Caspase-6 is important in the apoptotic signaling pathway; however, its role in non-apoptosis is also reported. Here, we first examined the non-apoptotic role of Caspase-6 in the alternative activation of macrophages after administration of IL-4, 4T1 tumor conditional medium, or co-culture with 4T1 cells. Both treatments promoted alternative activation of RAW264.7 cells and primary macrophages, whereas disruption of caspase-6 expression and activity could markedly suppress the biomarker levels of AAMs. Overexpression of Caspase-6 could significantly promote the activation of AAMs. Importantly, we further present evidence that caspase-6 could regulate breast cancer cell invasion by modulating MMP-2 and MMP-9 expression in 4T1 tumor-associated macrophages, as ablation of protein levels or activity of caspase-6 suppressed tumor cell invasion in vitro. In conclusion, the observed results markedly expanded our views of the dynamic changes in protein composition during alternative activation of macrophages, and they revealed a critical new role of caspase-6 in regulating this cellular biological process, which suggested that caspase-6 might be a key nod molecule to regulate immunological steady-state and be a therapeutic candidate for tumor immunotherapy.

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Section: Caspase-6-regulated Alternative Activation Of Macrophagessupporting

confidence: 78%

Identification of Caspase-6 as a New Regulator of Alternatively Activated Macrophages

Yao

Shi

Chen

et al. 2016

Journal of Biological Chemistry

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“…As previously stated, certain types of activated macrophages have been shown to produce IL-10 in sites of inflammation [56,57]. Notably, M2-activated macrophages, which are considered to be the majority of Tumorassociated macrophages (TAMs) within a tumor, release significant amounts of IL-10 [71], which could indicate a correlative rather than a causal relationship between IL-10 and tumor growth.…”

Section: The Potential Role Of Il-10 In Tumor Promotionmentioning

confidence: 94%

The paradoxical role of IL-10 in immunity and cancer

et al. 2015

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“…To examine this, we first made tumor-promoting macrophages that functionally and phenotypically resembled the TAMs in melanoma, by culturing peripheral blood monocytes in modified melanoma-conditioned media as previously described. 19 To demonstrate that these macrophages possessed tumor-promoting capacity, we cocultured macrophages and melanoma cell line A375 in separate compartments of a Transwell plate with a 0.4 µm membrane to physically separate direct contact while allowing the transmission of soluble factors. The melanoma cells with higher numbers of macrophages presented significantly better growth, thus demonstrating the tumorpromoting capacity of these macrophages ( Figure 2).…”

Section: Primary Tr1 Cells Eliminated Tumor-promoting Macrophagesmentioning

confidence: 99%

Primary Tr1 cells from metastatic melanoma eliminate tumor-promoting macrophages through granzyme B- and perforin-dependent mechanisms

Yan

Zhang²,

Kong

et al. 2017

Tumour Biol.

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In malignant melanoma, tumor-associated macrophages play multiple roles in promoting tumor growth, such as inducing the transformation of melanocytes under ultraviolet irradiation, increasing angiogenesis in melanomas, and suppressing antitumor immunity. Because granzyme B-and perforin-expressing Tr1 cells could specifically eliminate antigen-presenting cells of myeloid origin, we examined whether Tr1 cells in melanoma could eliminate tumor-promoting macrophages and how the interaction between Tr1 cells and macrophages could affect the growth of melanoma cells. Tr1 cells were characterized by high interleukin 10 secretion and low Foxp3 expression and were enriched in the CD4 + CD49b + LAG-3 + T-cell fraction. Macrophages derived from peripheral blood monocytes in the presence of modified melanoma-conditioned media demonstrated tumor-promoting capacity, exemplified by improving the proliferation of cocultured A375 malignant melanoma cells. But when primary Tr1 cells were present in the macrophage-A375 coculture, the growth of A375 cells was abrogated. The conventional CD25 + Treg cells, however, were unable to inhibit macrophage-mediated increase in tumor cell growth. Further analyses showed that Tr1 cells did not directly eliminate A375 cells, but mediated the killing of tumor-promoting macrophages through the secretion of granzyme B and perforin. The tumor-infiltrating interleukin 10 + Foxp3 − CD4 + T cells expressed very low levels of granzyme B and perforin, possibly suggested the downregulation of Tr1 cytotoxic capacity in melanoma tumors. Together, these data demonstrated an antitumor function of Tr1 cells through the elimination of tumor-promoting macrophages, which was not shared by conventional Tregs.

show abstract

Melanoma‐derived conditioned media efficiently induce the differentiation of monocytes to macrophages that display a highly invasive gene signature

Cited by 61 publications

References 51 publications

Identification of Caspase-6 as a New Regulator of Alternatively Activated Macrophages

Identification of Caspase-6 as a New Regulator of Alternatively Activated Macrophages

The paradoxical role of IL-10 in immunity and cancer

Primary Tr1 cells from metastatic melanoma eliminate tumor-promoting macrophages through granzyme B- and perforin-dependent mechanisms

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