261 Distinct Melanoma Cancer Stem Cell Profile Defines Response to Immune Checkpoint Inhibitors in Melanomas

Abstract

This study examined the relationship between cancer stem cells (CSCs) and the susceptibility of melanomas to immunotherapy. Immunotherapy has emerged as a pillar of cancer therapy, demonstrating marked survival benefits in patients with melanoma. However, there remains a significant number of patients who fail to respond to treatment. To improve patient outcomes and optimise appropriate drug selection, it is a priority to unravel the mechanisms underlying the emergence of drug resistance. One of the most important key players to have emerged in the development of drug resistance are the CSCs. Transcriptomic profiles of 158 melanoma biopsies from patients treated with anti-programmed cell death 1 ligand-1 (PD-1) monotherapy (nivolumab or pembrolizumab; n = 63) or combined anti-PD-1 and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4; ipilimumab; n = 57) were obtained. Patients were categorised as responders or non-responders using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, where responders had a complete response (CR), partial response (PR), or stable disease (SD) of greater than 6 months with no disease progression. Samples were analysed for differential gene expression after normalisation using DESeq2 and HTSeq. Gene levels of well-defined CSCs were compared between responders and non-responders. Changes to gene expression levels were also compared pre and post immunotherapy treatment. This analysis identified a unique melanoma CSC marker gene expression profile “signature” that corresponds to a positive response to immune checkpoint inhibitors. This gene expression profile was associated with longer progression-free survival in patients treated with immunotherapy agents. Therefore, we have identified a CSC gene expression profile that can be used to predict patient response to the current available anti-PD-1 or anti-CTLA4 based therapies. Furthermore, this helps with identifying patients in need of other therapeutic strategies.