Type I interferon signaling promotes radioresistance in head and neck cancer. Transl Cancer Res 2024 May 31;13(5):2535-2543
Date
06/17/2024Pubmed ID
38881922Pubmed Central ID
PMC11170510DOI
10.21037/tcr-23-2104Scopus ID
2-s2.0-85195040296 (requires institutional sign-in at Scopus site) 1 CitationAbstract
Despite the promise of concurrent radiotherapy (RT) and immunotherapy in head and neck cancer (HNC), multiple randomized trials of this combination have had disappointing results. To evaluate potential immunologic mechanisms of RT resistance, we compared pre-treatment HNCs that developed RT resistance to a matched cohort that achieved curative status. Gene set enrichment analysis demonstrated that a pre-treatment pro-immunogenic tumor microenvironment (TME), including type II interferon [interferon gamma (IFNγ)] and tumor necrosis factor alpha (TNFα) signaling, predicted cure while type I interferon [interferon alpha (IFNα)] enrichment was associated with an immunosuppressive TME found in tumors that went on to recur. We then used immune deconvolution of RNA sequencing datasets to evaluate immunologic cell subset enrichment. This identified M2 macrophage signaling associated with type I IFN pathway expression in RT-recurrent disease. To further dissect mechanism, we then evaluated differential gene expression between pre-treatment and RT-resistant HNCs from sampled from the same patients at the same anatomical location in the oral cavity. Here, recurrent samples exhibited upregulation of type I IFN-stimulated genes (ISGs) including members of the IFN-induced protein with tetratricopeptide repeats (IFIT) and IFN-induced transmembrane (IFITM) gene families. While several ISGs were upregulated in each recurrent cancer, IFIT2 was significantly upregulated in all recurrent tumors when compared with the matched pre-RT specimens. Based on these observations, we hypothesized sustained type I IFN signaling through ISGs, such as IFIT2, may suppress the intra-tumoral immune response thereby promoting radiation resistance.
Author List
Zenga J, Awan MJ, Frei A, Massey B, Bruening J, Shukla M, Sharma GP, Shreenivas A, Wong SJ, Zimmermann MT, Mathison AJ, Himburg HAAuthors
Jennifer D. Bruening MD Assistant Professor in the Otolaryngology department at Medical College of WisconsinHeather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin
Angela Mathison PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Joseph Zenga MD Associate Professor in the Otolaryngology department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin
