4.8 Article

Identification of a novel combination treatment strategy in clear cell renal cell carcinoma stem cells with shikonin and ipilimumab

Journal

FRONTIERS IN IMMUNOLOGY
Volume 14, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2023.1186388

Keywords

renal cell carcinoma; immune checkpoint inhibitor (ICI); phytochemical; immunotherapy; cancer stem cells (CSCs); tumor microenvironment (TME); tumor infiltrating immune cell (TIC)

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The management of ccRCC has changed rapidly with the introduction of ICIs, but many patients develop resistance to therapy. This study identifies shikonin as a promising combination partner with ipilimumab for the treatment of ccRCC, showing strong inhibitory effects on CSCs and activation of CD8+ and CD4+ T cells. Additionally, VCAM1 is identified as a potential immunotherapeutic target and novel CSC marker for ccRCC.
BackgroundManagement of clear cell renal cell carcinoma (ccRCC) has changed rapidly in recent years with the advent of immune checkpoint inhibitors (ICIs). However, only a limited number of patients can sustainably respond to immune checkpoint inhibitors and many patients develop resistance to therapy, creating an additional need for therapeutic strategies to improve the efficacy of systemic therapies. MethodsBinding probability and target genes prediction using online databases, invasion, migration, and apoptosis assays as well as the inhibition of cancer stem cells (CSCs) markers in ccRCC cell lines were used to select the most promising phytochemicals (PTCs). Mixed lymphocyte tumor cell culture (MLTC) system and flow cytometry were performed to confirm the potential combination strategy. The potential immunotherapeutic targets and novel CSC markers were identified via the NanoString analysis. The mRNA and protein expression, immune signatures as well as survival characteristics of the marker in ccRCC were analyzed via bioinformation analysis. ResultsShikonin was selected as the most promising beneficial combination partner among 11 PTCs for ipilimumab for the treatment of ccRCC patients due to its strong inhibitory effect on CSCs, the significant reduction of FoxP3(+) Treg cells in peripheral blood mononuclear cells (PBMCs) of patients and activation of the endogenous effector CD3(+)CD8(+) and CD3(+)CD4(+) T cells in response to the recognition of tumor specific antigens. Based on NanoString analysis VCAM1, CXCL1 and IL8 were explored as potential immunotherapeutic targets and novel CSC markers in ccRCC. The expression of VCAM1 was higher in the tumor tissue both at mRNA and protein levels in ccRCC compared with normal tissue, and was significantly positively correlated with immune signatures and survival characteristics in ccRCC patients. ConclusionWe propose that a combination of shikonin and ipilimumab could be a promising treatment strategy and VCAM1 a novel immunotherapeutic target for the treatment of ccRCC.

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