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Isolated limb perfusion with melphalan activates interferon-stimulated genes to induce tumor regression in patients with melanoma in-transit metastasis.

ABSTRACT: Hyperthermic isolated limb perfusion (ILP) with high-dose melphalan is a treatment option for melanoma patients with metastasis confined to limbs (in-transit metastasis). The therapy entails a complete response (CR) rate of 50-70%. Cellular immunity is proposed to impact on the clinical efficacy of ILP, but the detailed aspects of ILP-induced immune activation remain to be explored. For this study, we explored the potential role of interferon-stimulated gene (ISG) products, including CXCL10, CCL2, PD-L2 and IFN-γ along with expression of their cognate receptors CXCR3, CCR4, CCR5 and PD-1 on lymphocytes, for the clinical efficacy of ILP. Patients with high serum levels of CXCL10, CCL2, PD-L2 and IFN-γ were more likely to achieve CR after ILP. Additionally, the expression of CXCR3, CCR4 and CCR5 on T cells and/or natural killer (NK) cells was enhanced by ILP. Peripheral blood mononuclear cells (PBMCs) secreted high levels of CXCL10, CCL2 and IFN-γ in response to co-culture with melphalan-exposed melanoma cells in vitro. Activated T cells migrated toward supernatants from these co-cultures. Furthermore, melphalan-exposed melanoma cells triggered upregulation of CXCR3, CCR4, CCR5 and PD-1 on co-cultured T cells and/or NK cells. Our results suggest that constituents released from melphalan-exposed melanoma cells stimulate the ISG axis with ensuing formation of chemokines and upregulation of chemokine receptor expression on anti-neoplastic immune cells, which may contribute in ILP-induced tumor regression.

SUBMITTER: Johansson J

PROVIDER: S-EPMC6959433 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Isolated limb perfusion with melphalan activates interferon-stimulated genes to induce tumor regression in patients with melanoma in-transit metastasis.

Johansson Junko J Kiffin Roberta R Aydin Ebru E Nilsson Malin S MS Hellstrand Kristoffer K Lindnér Per P Naredi Peter P Olofsson Bagge Roger R Martner Anna A

Oncoimmunology 20191103 1

Hyperthermic isolated limb perfusion (ILP) with high-dose melphalan is a treatment option for melanoma patients with metastasis confined to limbs (in-transit metastasis). The therapy entails a complete response (CR) rate of 50-70%. Cellular immunity is proposed to impact on the clinical efficacy of ILP, but the detailed aspects of ILP-induced immune activation remain to be explored. For this study, we explored the potential role of interferon-stimulated gene (ISG) products, including CXCL10, CCL ...[more]

PMID: 32002296

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Project description:Isolated limb perfusion (ILP) involves the local administration of high doses of anticancer drugs into a limb affected by unresectable locally advanced tumors (with special regard to in-transit melanoma metastases), minimizing systemic side effects. Tumor response to anticancer drugs may depend on the expression of apoptosis-related genes, such as SURVIVIN and MDM2. This retrospective cohort study investigated the association between tumor SURVIVIN and MDM2 expression levels and treatment response or clinical outcomes in patients undergoing ILP for in-transit melanoma metastases. The study cohort consisted of 62 patients with in-transit metastases who underwent ILP with tumor necrosis factor (TNF) and melphalan. Tissue samples were taken from the in-transit metastases, and RNA was extracted for gene expression analysis. Patients' response to treatment was assessed using clinical and radiological criteria two months after ILP, and disease response was classified as complete, partial, or stable/progressive disease. Disease-free survival (DFS) and overall survival (OS) were also analyzed. Expression of SURVIVIN and/or MDM2 was observed in 48% of patients; in these cases, complete response to ILP occurred in 40% of cases, with the overall response rate (complete + partial) being 85%. Patients with expression of MDM2 alone had a lower complete response rate (28%), while patients with expression of SURVIVIN alone had a higher complete response rate (50%). The combined expression of MDM2 and SURVIVIN resulted in a complete response rate of 30%. Patients without expression (of SURVIVIN or MDM2) had the highest complete response rate (58%). Survival analysis showed that high MDM2 expression was independently associated with a lower probability of a complete response to ILP. In addition, patients with MDM2 expression were three times more likely to have an incomplete response to ILP. This study highlights the importance of considering SURVIVIN and MDM2 expression in patients undergoing ILP for in-transit cutaneous melanoma metastases. High MDM2 expression was found to be an independent factor associated with a reduced likelihood of achieving a complete response to ILP, suggesting potential mechanisms of chemoresistance. These data support further research to explore the role of already available targeted therapies (i.e., MDM2 inhibitors) in improving tumor response to ILP in patients with in-transit melanoma metastases.

Dataset Information

Isolated limb perfusion with melphalan activates interferon-stimulated genes to induce tumor regression in patients with melanoma in-transit metastasis.

Publications

Isolated limb perfusion with melphalan activates interferon-stimulated genes to induce tumor regression in patients with melanoma in-transit metastasis.

Similar Datasets

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