Identification of the transcriptomic alterations of resistance to immune checkpoint inhibitors in melanoma

Abstract

Although immunotherapeutics like immune checkpoint inhibitor (ICI) therapy have greatly improved survival rates, death rates of melanoma still remain high. One of the reasons for this is that the solid tumor microenvironment creates obstacles for the effectiveness of anti-PD1 immunotherapy in patients. Therefore, it is crucial to identify potential biomarkers that could be used in combination therapy with anti-PD1 to modify the tumor microenvironment and enhance response to treatment. In this study, we examined clinical and tumor transcriptional sequencing data from 91 patients who received anti-PD1/anti-CTLA4 therapy. Through both bulk RNA sequencing analysis and single-cell RNA-sequencing (scRNA-seq), we discovered that 8 key pathways were upregulated in patients who responded well to the therapy. Interestingly, these pathways were found in myeloid and T cell populations, indicating their significant role in response to anti-PD1/anti-CTLA4 therapy. Among these pathways, genes such as IRF1, IRF2, C1, and C3 emerged as potential biomarkers that could potentially enhance the effectiveness of ICIs therapy. Further clinical research is required to validate the impact of these genes. The novelty of this study lies in the combination of bulk RNA sequencing and single RNA sequencing methods, which allowed us to uncover distinct differences in the transcriptomic landscape of solid tumors, particularly melanoma.