Cancer stem cells establish intrinsic immune resistance through suppressing IFN-mediated antitumor immunity 3113

Abstract Description Although cancer immunotherapy has shown promising clinical outcomes, many cancer patients exhibit resistance or relapse after an initial response. This issue is particularly urgent for patients with squamous cell carcinomas (SCCs), underscoring the critical need to understand immune evasion and immunotherapy resistance in these cancers. Recently, our lab identified a subset of tumor-initiating stem cells (tSCs) in skin and head/neck SCCs that respond to transforming growth factor β (TGFβ) and play a key role in driving tumor relapse post-immunotherapy. Notably, these tSCs are resistant to T-cell attacks despite retaining functional antigen presentation, resulting in only transient responses to immune checkpoint blockade therapy across SCC types. Here, my current study has uncovered a central role for Sox2 as a master regulator driving immune resistance in TGFβ-responsive tSCs. Through RNA-seq and qPCR analyses, we observed that Sox2 amplification in tSCs significantly blunts their interferon-γ (IFNγ) responsive potentials. Mechanistically, we found that Sox2 neither blocks IFNγ signal transduction nor directly binds to the enhancers or promoters of most IFNγ-induced genes. Instead, the reduced IFNγ response in Sox2-overexpressing cells stems from altered Stat1-mediated transcriptional repression. This study uncovered a stem cell-specific transcriptional regulation, providing insights for developing new strategies to overcome tSC-specific immune resistance. Funding Sources Supported by R01CA285786 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)