AUTHOR=Yu Yang , Tang Huiwen , Franceschi Debora , Mujagond Prabhakar , Acharya Aneesha , Deng Yupei , Lethaus Bernd , Savkovic Vuk , Zimmerer Rüdiger , Ziebolz Dirk , Li Simin , Schmalz Gerhard TITLE=Immune Checkpoint Gene Expression Profiling Identifies Programmed Cell Death Ligand-1 Centered Immunologic Subtypes of Oral and Squamous Cell Carcinoma With Favorable Survival JOURNAL=Frontiers in Medicine VOLUME=8 YEAR=2022 URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.759605 DOI=10.3389/fmed.2021.759605 ISSN=2296-858X ABSTRACT=Objective

This study aimed to identify the programmed death ligand-1 (PDL1, also termed as CD274) and its positively correlated immune checkpoint genes (ICGs) and to determine the immune subtypes of CD274-centered ICG combinations in oral and squamous cell carcinoma (OSCC).

Materials and Methods

Firstly, the 95 ICGs obtained via literature reviews were identified in the Cancer Genome Atlas (TCGA) database in relation to OSCC, and such 88 ICG expression profiles were extracted. ICGs positively correlated with CD274 were utilized for subsequent analysis. The relationship between ICGs positively correlated with CD274 and immunotherapy biomarkers (tumor mutation burden (TMB), and adaptive immune resistance pathway genes) was investigated, and the relationships of these genes with OSCC clinical features were explored. The prognostic values of CD274 and its positively correlated ICGs and also their associated gene pairs were revealed using the survival analysis.

Results

Eight ICGs, including CTLA4, ICOS, TNFRSF4, CD27, B- and T-lymphocyte attenuator (BTLA), ADORA2A, CD40LG, and CD28, were found to be positively correlated with CD274. Among the eight ICGs, seven ICGs (CTLA4, ICOS, TNFRSF4, CD27, BTLA, CD40LG, and CD28) were significantly negatively correlated with TMB. The majority of the adaptive immune resistance pathway genes were positively correlated with ICGs positively correlated with CD274. The survival analysis utilizing the TCGA-OSCC data showed that, although CD274 was not significantly associated with overall survival (OS), the majority of ICGs positively correlated with CD274 (BTLA, CD27, CTLA4, CD40LG, CD28, ICOS, and TNFRSF4) were significantly correlated with OS, whereby their low-expression predicted a favorable prognosis. The survival analysis based on the gene pair subtypes showed that the combination subtypes of CD274_low/BTLA_low, CD274_low/CD27_low, CD274_low/CTLA4_low, CD8A_high/BTLA_low, CD8A_high/CD27_low, and CD8A_high/CTLA4_low predicted favorable OS.

Conclusion

The results in this study provide a theoretical basis for prognostic immune subtyping of OSCC and highlight the importance of developing future immunotherapeutic strategies for treating oral cancer.