Abstract
ObjectiveSquamous cell carcinomas (SCCs) with shared etiology, histological characteristics, and certain risk factors represent the most common solid cancers. This study reports the crosstalk between autophagy and ferroptosis at the molecular level in SCCs, and their roles on the immunological tumor microenvironment (TME) of SCCs.MethodsIn this study, the connections between autophagy and ferroptosis were characterized in SCCs by analyzing the associations between autophagy- and ferroptosis-related genes in mRNA expression and prognosis, protein-protein interactions and shared signaling pathways. Autophagy potential index (API) and ferroptosis potential index (FPI) of each tumor were quantified for reflecting autophagy and ferroptosis levels via principal-component analysis algorithm. Their synergistical roles on TME, immunity, drug resistance and survival were systematically analyzed in SCCs.ResultsThere were close connections between autophagy and ferroptosis at the mRNA and protein levels and prognosis. Both shared cancer-related pathways. The API and FPI were separately developed based on prognostic autophagy- and ferroptosis-related genes. A high correlation between API and FPI was found in SCCs. Their interplay was distinctly associated with favorable prognosis, enhanced sensitivity to chemotherapy drugs (Sunitinib, Gefitinib, Vinblastine and Vorinostat), an inflamed TME and higher likelihood of response to immunotherapy in SCCs.ConclusionThis study is the first to provide a comprehensive analysis of the interplay between autophagy and ferroptosis and their synergistical roles on manipulating the immunological TME in SCCs. These findings indicated that the induction of autophagy and ferroptosis combined with immunotherapy might produce synergistically enhanced anti-SCCs activity.
Highlights
Squamous cell carcinomas (SCCs) represent the most common solid cancers [1]
Their interplay was distinctly associated with favorable prognosis, enhanced sensitivity to chemotherapy drugs (Sunitinib, Gefitinib, Vinblastine and Vorinostat), an inflamed tumor microenvironment (TME) and higher likelihood of response to immunotherapy in squamous cell carcinomas (SCCs)
This study is the first to provide a comprehensive analysis of the interplay between autophagy and ferroptosis and their synergistical roles on manipulating the immunological TME in SCCs
Summary
Squamous cell carcinomas (SCCs) represent the most common solid cancers [1]. SCCs arise from epithelial tissues of the aerodigestive or genitourinary tracts, which are commonly detected in head and neck, esophagus, lung, and cervix [2]. SCCs across different body sites share overlapping etiology, histopathological characteristics [such as the presence of keratin pearls, tonofilament bundles, hemidesmosomes and desmosomes [3]] and specific risk factors (such as smoking, drinking and human papillomavirus infection) [4]. Previous the Cancer Genome Atlas (TCGA) research has uncovered that SCCs exhibit similar molecular patterns such as somatic mutations, copy number variations, abnormal pathways, and tumor microenvironment (TME) that differ from other cancer types [2, 5, 6]. Treatment with immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 (anti-PD-1), anti-programmed death ligand-1 (anti-PD-L1), and/or anti-cytotoxic T lymphocyteassociated antigen-4 (anti-CTLA-4) has been applied to SCCs, which can result in impressive response rates and durable disease remission in clinical trials [8,9,10]. Only in a subset of patients respond to ICI therapy [11]
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