Protein methyltransferases and demethylases dictate CD8+ T-cell exclusion in squamous cell carcinoma of the head and neck
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Theodore Vougiouklakis1,*, Riyue Bao2,3,*, Yusuke Nakamura1,4 and Vassiliki Saloura1,5
1Department of Medicine, University of Chicago, Chicago, IL, USA
2Center for Research Bioinformatics, University of Chicago, Chicago, IL, USA
3Department of Pediatrics, University of Chicago, Chicago, IL, USA
4Department of Surgery, University of Chicago, Chicago, IL, USA
5Center for Cancer Research, National Cancer Institute, Chicago, IL, USA
*These authors have contributed equally to this paper
Vassiliki Saloura, email: [email protected]
Keywords: squamous cell carcinoma of head and neck; protein methyltransferases; immune markers
Received: September 08, 2017 Accepted: October 13, 2017 Published: November 22, 2017
A subset of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) benefit from pembrolizumab and nivolumab, but the majority of patients do not probably due to lack of activated cytotoxic CD8+ T-cells in their tumor tissues. Herein, we aim to investigate whether specific protein methyltransferases (PMTs) and demethylases (PDMTs) could play any roles in the CD8+ T-cell exclusion process in HPV-negative SCCHN. RNA sequencing data from the TCGA database were interrogated for HPV-negative SCCHN patients using a 10-gene chemokine signature that classifies SCCHN tissues into CD8+ T-cell inflamed and non-CD8+ T-cell inflamed phenotypes. Among 53 PMT/PDMT genes examined in the TCGA HPV-negative SCCHN database, expression levels of 15 PMT/PDMT genes were significantly negatively correlated with the chemokine signature score and CD8 mRNA expression levels. The expression level of each of these 15 PMT/PDMT genes showed significantly negative correlations with immune-active chemokines, as well as HLA class I and APM molecules. siRNA-mediated knockdown of a candidate PMT, SMYD3, led to upregulation of CXCL9, CXCL10, CXCL11 and TAP1 at mRNA and protein levels in HPV-negative SCCHN cell lines. These findings demonstrate that overexpression of some PMTs and PDMTs seems to be related with the non-CD8+ T-cell inflamed phenotype and may drive CD8+ T-cell exclusion in HPV-negative SCCHN. This study suggests that chromatin modifiers contribute to CD8+ T-cell exclusion and antigen presentation capacity of HPV-negative SCCHN, supporting that targeting of specific PMTs and/or PDMTs could enhance CD8+ T-cell infiltration and increase the proportion of patients that may benefit from immunotherapy.
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