Background: Management 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. Methods: Binding 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.
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. Conclusion: We 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.
In , this therapy was approved for previously untreated RCC patients with intermediate and low risk 7. Furthermore, in a recent phase 3 clinical trial NCT , the combination of cabozantinib, nivolumab, and ipilimumab demonstrated statistically significant improvements in progression-free survival PFS among participants.
Despite significant improvements in systemic therapies for ccRCC, only a few patients have achieved a durable clinical response, with the median PFS ranging from Additional therapeutic strategies to improve the efficacy of systemic therapies are therefore urgently needed, especially in patients with limited disease burden. Targeting cancer stem cells CSCs , a small population of cancer cells in the tumor microenvironment TME , has been suggested as the key to successful treatment against the increased relapse rate of cancers toward current chemo- or radiotherapy Emerging evidence has indicated that renal tumorigenesis and RCC treatment resistance may originate from renal CSCs with tumor-initiating capacity 11 , Therefore, the identification of a specific CSC marker for RCC that either initiate or maintain tumorigenesis is of most importance for understanding tumor biology and in the development of novel therapies.
