Melanoma: tumor microenvironment and new treatments

Giavina-Bianchi, Mara Huffenbaecher; Junior, Pedro Francisco Giavina-Bianchi; Neto, Cyro Festa

doi:10.1590/abd1806-4841.20176183

Cited by 37 publications

(33 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accumulating researches have highlighted the crucial role of cancer microenvironment in melanoma and CRC progression, metastasis and evasion of the immune surveillance. 20,21 In this study, we found that the quantity of CAFs in melanoma and CRC were positively correlated with PD-L1 expression. CAFs and the derivation, CXCL5, promoted the expression of PD-L1 in mice melanoma and CRC cancer cells via PI3K/AKT signaling pathways.…”

Section: Discussionsupporting

confidence: 50%

See 1 more Smart Citation

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

Zhou

Zhang

et al. 2019

Intl Journal of Cancer

141

131

View full text Add to dashboard Cite

Cancer‐associated fibroblasts (CAFs) play a key role in orchestrating the tumor malignant biological properties within tumor microenvironment and evidences demonstrate that CAFs are a critical regulator of tumoral immunosuppression of the T cell response. However, the functions and regulation of CAFs in the expression of programmed death‐ligand 1 (PD‐L1) in melanoma and colorectal carcinoma (CRC) are not completely understood. Herein, by scrutinizing the expression of α‐SMA and PD‐L1 in melanoma and CRC tissues, we found that CAFs was positive correlated with PD‐L1 expression. Further analyses showed that CAFs promoted PD‐L1 expression in mice tumor cells. By detecting a majority of cytokines expression in normal mice fibroblasts and CAFs, we determined that CXCL5 was abnormal high expression in CAFs and the immunohistochemistry and in situ hybridization confirmed that were CAFs which were expressing CXCL5. In addition, CXCL5 promoted PD‐L1 expression in B16, CT26, A375 and HCT116. The silencing of CXCR2, the receptor of CXCL5, inhibited the PD‐L1 expression induced by CAFs in turn. Functionally, CXCL5 derived by CAFs promoted PD‐L1 expression in mice tumor cells through activating PI3K/AKT signaling. LY294002, the inhibitor of PI3K, confirmed that CXCL5 forested an immunosuppression microenvironment by promoting PD‐L1 expression via PI3K/AKT signaling. Meanwhile, the B16/CT26 xenograft tumor models were used and both CXCR2 and p‐AKT were found to be positively correlated with PD‐L1 in the xenograft tumor tissues. The immunosuppressive action of CAFs on tumor cells is probably reflective of them being a potential therapeutic biomarker for melanoma and CRC.

show abstract

Section: Discussionsupporting

confidence: 50%

“…Accumulating researches have highlighted the crucial role of cancer microenvironment in melanoma and CRC progression, metastasis and evasion of the immune surveillance . In this study, we found that the quantity of CAFs in melanoma and CRC were positively correlated with PD‐L1 expression.…”

Section: Discussionmentioning

confidence: 52%

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

Zhou

Zhang

et al. 2019

Intl Journal of Cancer

141

131

View full text Add to dashboard Cite

show abstract

“…As accumulating investigations have proved the importance of TME modulation in alleviating the offensive behavior of melanoma 20 , 21 , we hypothesize that targeted delivery of Frax to the tumor site will lead to deactivation of TAFs and reduce tumor load. Nevertheless, remodeling TME alone might affect tumor growth partially.…”

Section: Introductionmentioning

confidence: 97%

Nano-delivery of fraxinellone remodels tumor microenvironment and facilitates therapeutic vaccination in desmoplastic melanoma

et al. 2018

View full text Add to dashboard Cite

Rationale: Tumor-associated fibroblasts (TAFs) play a critical role in the suppressive immune tumor microenvironment (TME), compromising the efficacy of immunotherapy. To overcome this therapeutic hurdle, we developed a nanoemulsion (NE) formulation to deliver fraxinellone (Frax), an anti-fibrotic medicine, to TAFs, as an approach to reverse immunosuppressive TME of desmoplastic melanoma.Methods: Frax NE was prepared by an ultrasonic emulsification method. The tumor inhibition effect was evaluated by immunofluorescence staining, masson trichrome staining and western blot analysis. Immune cell populations in tumor and LNs were detected by flow cytometry.Results: This Frax NE, with a particle size of around 145 nm, can efficiently accumulate in the tumor site after systemic administration and was taken up by TAFs and tumor cells. A significant decrease in TAFs and stroma deposition was observed after intravenous administration of Frax NE, and Frax NE treatment also remolded the tumor immune microenvironment, as was reflected by an increase of natural-killer cells, cytotoxic T cells (CTLs) as well as a decrease of regulatory B cells, and myeloid-derived suppressor cells in the TME. In addition, after treatment by Frax NEs, T helper 1 (Th1) cytokines of interferon gamma (IFN-γ), which effectively elicit anti-tumor immunity, were enhanced. Transforming growth factor-β (TGF-β), chemokine (C-C motif) ligand 2 (CCL2) and interleukin 6 (IL6), which inhibit the development of anti-tumor immunity, were reduced. Although Frax NE demonstrated an inhibitory effect on tumor growth, this mono-therapy could only achieve partial antitumor efficacy, and the tumor growth effect was not maintained long-term after dosing stopped. Therefore, a tumor-specific peptide vaccine was combined with Frax NEs. The combination led to enhanced tumor-specific T-cell infiltration, activated death receptors on the tumor cell surface, and induced increased apoptotic tumor cell death.Conclusion: Collectively, Frax NE combined with tumor-specific peptide vaccine might be an effective and safe strategy to remodel fibrotic TME, thereby enhancing immune response activation, resulting in a prolonged efficiency for advanced desmoplastic melanoma.

show abstract

“…These include monoclonal antibodies: Vemurafenib, Dabrafenib, Trametinib, Ipilimumab (anti-CTLA4), Pembrolizumab (anti-PD-1) and Nivolumab (anti-PD-1), and anti-proliferative cytokine used as adjuvant: Peginterferon alfa-2b. Cancer immunotherapy is a promising and specific therapeutic strategy for melanoma treatment and may involve passive antibody transfer, adoptive transfer of T cells and therapeutic vaccines [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

M1-like macrophages change tumor blood vessels and microenvironment in murine melanoma

et al. 2018

View full text Add to dashboard Cite

Tumor-associated macrophages (TAMs) play a significant role in at least two key processes underlying neoplastic progression: angiogenesis and immune surveillance. TAMs phenotypic changes play important role in tumor vessel abnormalization/ normalization. M2-like TAMs stimulate immunosuppression and formation of defective tumor blood vessels leading to tumor progression. In contrast M1-like TAMs trigger immune response and normalize irregular tumor vascular network which should sensitize cancer cells to chemo- and radiotherapy and lead to tumor growth regression. Here, we demonstrated that combination of endoglin-based DNA vaccine with interleukin 12 repolarizes TAMs from tumor growth-promoting M2-like phenotype to tumor growth-inhibiting M1-like phenotype. Combined therapy enhances tumor infiltration by CD4+, CD8+ lymphocytes and NK cells. Depletion of TAMs as well as CD8+ lymphocytes and NK cells, but not CD4+ lymphocytes, reduces the effect of combined therapy. Furthermore, combined therapy improves tumor vessel maturation, perfusion and reduces hypoxia. It caused that suboptimal doses of doxorubicin reduced the growth of tumors in mice treated with combined therapy. To summarize, combination of antiangiogenic drug and immunostimulatory agent repolarizes TAMs phenotype from M2-like (pro-tumor) into M1-like (anti-tumor) which affects the structure of tumor blood vessels, improves the effect of chemotherapy and leads to tumor growth regression.

show abstract

Melanoma: tumor microenvironment and new treatments

Cited by 37 publications

References 91 publications

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

Nano-delivery of fraxinellone remodels tumor microenvironment and facilitates therapeutic vaccination in desmoplastic melanoma

M1-like macrophages change tumor blood vessels and microenvironment in murine melanoma

Contact Info

Product

Resources

About