Anti-PD1 and Anti-PD-L1 in the Treatment of Metastatic Melanoma

Simeone, Ester; Grimaldi, Antonio; Ascierto, Paolo A.

doi:10.2217/mmt.14.30

Cited by 6 publications

(4 citation statements)

References 41 publications

(54 reference statements)

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“…Monoclonal antibodies directed against the immune checkpoints – such as CTLA-4 (ipilimumab), PD-1 (nivolumab and pembrolizumab), or PD-L1 (BMS936559, MPDL3280A, and MEDI4736) – have been demonstrated to achieve durable antitumoral responses with significantly prolonged overall survivals in patients with metastatic melanoma ( 8 ). Despite the increased attention is currently paid to cancer immunotherapy (especially, treatments targeting PD-1/PD-L1 molecules) – which may become the standard of care in treating all unresectable stage III and IV melanomas, regardless of the BRAF mutational status, we here focused on molecular mechanisms involved in development and progression of the disease.…”

Section: Introductionmentioning

confidence: 99%

Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets

et al. 2015

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Molecular mechanisms involved in pathogenesis of malignant melanoma have been widely studied and novel therapeutic treatments developed in recent past years. Molecular targets for therapy have mostly been recognized in the RAS–RAF–MEK–ERK and PI3K–AKT signaling pathways; small-molecule inhibitors were drawn to specifically target key kinases. Unfortunately, these targeted drugs may display intrinsic or acquired resistance and various evidences suggest that inhibition of a single effector of the signal transduction cascades involved in melanoma pathogenesis may be ineffective in blocking the tumor growth. In this sense, a wider comprehension of the multiple molecular alterations accounting for either response or resistance to treatments with targeted inhibitors may be helpful in assessing, which is the most effective combination of such therapies. In the present review, we summarize the known molecular mechanisms underlying either intrinsic and acquired drug resistance either alternative roads to melanoma pathogenesis, which may become targets for innovative anticancer approaches.

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Section: Introductionmentioning

confidence: 99%

Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets

et al. 2015

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“…Immunotherapy is one important method for melanoma treatment, when alone or in combination with anti-PD-1 and anti-PD-L1 may improve survival rates ( Simeone, Grimaldi & Ascierto, 2015 ). Nivolumab is a PD-1 inhibitor with high affinity to PD-1 ( Hirano et al, 2005 ).…”

Section: Discussionmentioning

confidence: 99%

Sema4D silencing increases the sensitivity of nivolumab to B16-F10 resistant melanoma via inhibiting the PI3K/AKT signaling pathway

Zhang

Wang

et al. 2023

PeerJ

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Melanoma is a common skin tumor that causes a high rate of mortality, especially in Europe, North America and Oceania. Immunosuppressants such as anti-PD-1 have been used in the treatment of malignant melanoma, however, nearly 60% of patients do not respond to these treatments. Sema4D, also called CD100, is expressed in T cells and tumor tissues. Sema4D and its receptor, Plexin-B1, play crucial roles in the process of immune regulation, angiogenesis, and tumor progression. The role of Sema4D in melanoma with anti-PD-1 resistance is poorly understood. Through a combination of molecular biology techniques and in silico analysis, the role of Sema4D in improving anti-PD-L1 sensitivity in melanoma was explored. The results showed that the expression of Sema4D, Plexin-B1 and PD-L1 was significantly increased in B16-F10R cells. Sema4D knockdown synergizes with anti-PD-1 treatment, cell viability, cell invasion and migration were significantly decreased, while the apoptosis was increased, the growth of tumors on the mice was also inhibited. Mechanistically, bioinformatics analysis revealed that Sema4D is involved in the PI3K/AKT signaling pathway; the downregulation of p-PI3K/PI3K and p-AKT/AKT expression were observed in Sema4D knockdown, therefore, nivolumab resistance is related to Sema4D and Sema4D silencing can improve sensitivity to nivolumab via inhibition of the PI3K/AKT signaling pathway.

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“…It's typical clinical manifestations includes bloody diarrhea, abdominal pain, fecal urgency, and tenesmus, while anemia, fatigue and poor appetite as the concomitant symptom are also prevalent 2,3 . Autoimmune disease feaures the abnormalities of innate and adaptive immune responses, which also underlies the pathogenesis of UC 4–9 . Recent studies have shown that regimens to regulate the Th17/Treg cell balance could suppress autoimmune diseases pathogenesis and progression 7–9 .…”

Section: Introductionmentioning

confidence: 99%

“… 2 , 3 Autoimmune disease feaures the abnormalities of innate and adaptive immune responses, which also underlies the pathogenesis of UC. 4 , 5 , 6 , 7 , 8 , 9 Recent studies have shown that regimens to regulate the Th17/Treg cell balance could suppress autoimmune diseases pathogenesis and progression. 7 , 8 , 9 Unbalanced intestinal immune homeostasis caused by excessive activation of T cells was one of the important characteristics of UC, which leads to the release of pro‐inflammatory mediators, the abnormal aggregation of immune cells and the destruction of intestinal mucosal tissue.…”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicles produced by bone marrow mesenchymal stem cells overexpressing programmed death‐ligand 1 ameliorate dextran sodium sulfate‐induced ulcerative colitis in rats by regulating Th17/Treg cell balance through PTEN/PI3K/AKT/mTOR axis

Chen

Fan

et al. 2022

J of Gastro and Hepatol

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Background and Aim Programmed death‐ligand 1 (PD‐L1) was involved in regulating Th17/Treg cell balance in ulcerative colitis (UC). Extracellular vesicles (EVs) from genetically modified bone marrow mesenchymal stem cells (BMSCs) can serve as a stable delivery system to overexpress PD‐L1. The study was designed to evaluate the therapeutic mechanism of BMSC‐EVs overexpressing PD‐L1 (PD‐L1‐EVs) on ulcerative colitis. Methods Experimental model of UC was established in rats by drinking 5% dextran sulfate sodium (DSS). Apoptosis‐related proteins, inflammatory response‐related factors and oxidative stress related mediators were detected. Westernblot was used to detecte key proteins in the PI3K/AKT signaling pathway and its downstream effectors. The CD4+Foxp3+Treg cells and CD4+IL‐17A+Th17 cells in spleen and mesenteric lymph nodes (MLNs) was detected by flow cytometry. Results PD‐L1‐EVs significantly alleviated the manifestations and pathological damage of UC rats by inhibiting the expression of IFN‐γ, IL‐1β, IL‐8, IL‐6, IL‐2, BAX, NF‐κB, TNF‐α, MPO, and MDA, and up‐regulating the expression of IL‐4, BCL‐2, SOD, and GSH. Furthermore, the proportions of Th17 cells were decreased and that of Treg cells were upregulated by PD‐L1‐EVs treatment. PTEN inhibitors (bpv) partially abolished the inhibitory effect of PD‐L1‐EVs on PI3K‐AKT signaling and impaired the therapeutic efficacy of PD‐L1‐EVs. Conclusions PD‐L1‐EVs mitigated colonal inflammation, apoptosis and oxidative stress through blocking the activation of PI3K/Akt/mTOR pathway and regulating the balance of Th17/Treg cells.

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Anti-PD1 and Anti-PD-L1 in the Treatment of Metastatic Melanoma

Cited by 6 publications

References 41 publications

Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets

Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets

Sema4D silencing increases the sensitivity of nivolumab to B16-F10 resistant melanoma via inhibiting the PI3K/AKT signaling pathway

Extracellular vesicles produced by bone marrow mesenchymal stem cells overexpressing programmed death‐ligand 1 ameliorate dextran sodium sulfate‐induced ulcerative colitis in rats by regulating Th17/Treg cell balance through PTEN/PI3K/AKT/mTOR axis

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