Immunomodulatory Factors Control the Fate of Melanoma Tumor Initiating Cells

Abstract

Melanoma is a highly heterogeneous tumor for which recent evidence supports a model of dynamic stemness. Melanoma cells might temporally acquire tumor-initiating properties or switch from a status of tumor-initiating cells (TICs) to a more differentiated one depending on the tumor context. However, factors driving these functional changes are still unknown. We focused on the role of cyto/chemokines in shaping TICs isolated directly from tumor specimens of two melanoma patients, namely Me14346S and Me15888S. We analyzed the secretion profile of TICs and of their corresponding melanoma differentiated cells and we tested the ability of cyto/chemokines to influence TIC self-renewal and differentiation. We found that TICs, grown in vitro as melanospheres, had a complex secretory profile as compared to their differentiated counterparts. Some factors, such as CCL-2 and IL-8, also produced by adherent melanoma cells and melanocytes did not influence TIC properties. Conversely, IL-6, released by differentiated cells, reduced TIC self-renewal and induced TIC differentiation while IL-10, produced by Me15888S, strongly promoted TIC self-renewal through paracrine/autocrine actions. Complete neutralization of IL-10 activity by gene silencing and antibody-mediated blocking of the IL-10Rα was required to sensitize Me15888S to IL-6-induced differentiation. For the first time these results show that functional heterogeneity of melanoma could be directly influenced by inflammatory and suppressive soluble factors, with IL-6 favoring TIC differentiation, and IL-10 supporting TIC self-renewal. Thus, understanding the tumor microenvironment (TME) role in modulating melanoma TIC phenotype is fundamental to identifying novel therapeutic targets to achieve long-lasting regression of metastatic melanoma. Stem Cells 2016;34:2449-2460.

Mechanism of resistance to immune checkpoint inhibitors

“…Immune suppressive factors in the tumor microenvironment TME have also been suggested as pathways of resistance. Tumor-derived immunosuppressive cytokines, like IL-10 and exosomes, have been noted [95,96] . These observations will lead to novel combinatorial therapies directed at these pathways.…”

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“…13 Indeed, anti-CTLA4 monoclonal antibodies, ipilimumab and tremelimumab have shown promise in clinical trials 11,14 in patients with metastatic melanoma. Tuccito et al 15 were able to demonstrate another effective means to modifying the immunologic tumor microenvironment. They demonstrated that interleukin-6 (an inflammatory cytokine) released from differentiated melanoma cells reduced MSC self-renewal and instead induced differentiation.…”

“…By silencing interluekin-10 by blocking the IL-10 receptor. Tuccito et al 15 were able to sensitize MSCs to interleukin-6 and thus induce MSC differentiation. Through these cytokine manipulations, they were able to decrease MSC self-renewal capacity, and instead differentiate stem cells to a more easily targeted phenotype.…”

“…Through these cytokine manipulations, they were able to decrease MSC self-renewal capacity, and instead differentiate stem cells to a more easily targeted phenotype. 15 Du et al have recently shown how to use stem cells as an ally (rather than an enemy) in treatment of metastatic melanoma to the brain. In the mouse model, they successfully demonstrated the utility of mesenchymal stem cells to carry oncolytic herpes simplex virus through intracarotid administration to metastatic brain lesions and deliver the oncolytic viruses.…”

Cancer Stem Cells: «Emergency Service» for Tumors Under Generalized Cellular Stress

“…обладающих бесконечным пролиферативным потенциалом, но не обладающих низкодифференцированным фенотипом, in vivo стволовые раковые клетки могут возникать de novo, давая начало опухоли. Такая модель «динамической стволовости» показана, в частности, для меланом, клетки которых могут временно приобретать «рак-инициирующие» свойства, а также переходить из состояния «инициирующих клеток» в более дифференцированное в зависимости от опухолевого контекста [22]. В других работах также была показана возможность перехода раковых клеток в обоих направлениях от клеток с признаками стволовых клеток к дифференцированным клеткам и обратно [23,24].…”