Abstract
The tumor immune microenvironment of oral tongue squamous cell carcinoma may be accountable for differences in clinical behavior, particularly between different age groups. We performed RNA expression profiling and evaluated tumor infiltrating lymphocytes (TILs) and their T-cell subsets in order to assess the functional status of oral tongue squamous cell carcinoma tumor microenvironment and detect potentially clinically useful associations. Archival surgical pathology material from sixteen oral tongue squamous cell carcinoma patients was microscopically evaluated for TIL densities. RNA was extracted from macrodissected whole tumor sections and normal controls and RNA expression profiling was performed by the NanoString PanCancer IO 360 Gene Expression Panel. Immunostains for CD4, CD8 and FOXP3 were evaluated manually and by digital image analysis. Oral tongue squamous cell carcinomas had increased TIL densities, numerically dominated by CD4 + T cells, followed by CD8 + and FOXP3 + T cells. RNA expression profiling of tumors versus normal controls showed tumor signature upregulation in inhibitory immune signaling (CTLA4, TIGIT and PD-L2), followed by inhibitory tumor mechanisms (IDO1, TGF-β, B7-H3 and PD-L1). Patients older than 44 years showed a tumor microenvironment with increased Tregs and CTLA4 expression. Immunohistochemically assessed CD8% correlated well with molecular signatures related to CD8 + cytotoxic T-cell functions. FOXP3% correlated significantly with CTLA4 upregulation. CTLA4 molecular signature could be predicted by FOXP3% assessed by immunohistochemistry (R2 = 0.619, p = 0.026). Oral tongue squamous cell carcinoma hosts a complex inhibitory immune microenvironment, partially reflected in immunohistochemically quantified CD8 + and FOXP3 + T-cell subsets. Immunohistochemistry can be a useful screening tool for detecting tumors with upregulated expression of the targetable molecule CTLA4.
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Abbreviations
- HPV:
-
Human papillomavirus
- TILs:
-
Tumor infiltrating lymphocytes
- PD-L1:
-
Programmed death ligand 1
- FOXP3:
-
Forkhead box P3
- CTLA4:
-
Cytotoxic T lymphocyte-associated protein 4
- TIGIT:
-
T cell immunoreceptor with Ig and ITIM domains
- PD-L2:
-
Programmed death ligand 2
- IDO1:
-
Indoleamine-pyrrole 2,3-dioxygenase 1
- TGF-β:
-
Transforming growth factor beta
- Tregs:
-
Regulatory T cells
- PD-1:
-
Programmed cell death protein 1
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Acknowledgements
Administrative Support: The authors would like to thank Mayo Clinic Research and Innovation Office for the exceptional administrative support. Expert Opinion: The authors thank Dr. Michael Rivera, M.D. for his expert opinion on immunohistochemistry interpretation.
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Mayo Clinic Institutional Research Funds. The funders had no role in designing the study, collecting and analyzing the data, drafting the manuscript or making the decision to publish.
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KC—Conceptualized part of the study, collected and reviewed histologic material, interpreted immunohistochemical studies and results and wrote the manuscript. SS—Reviewed histologic material, immunohistochemical slides, performed the digital image analysis, reviewed and critically edited the manuscript. ARC—Collected and reviewed histologic material, interpreted results, reviewed and critically edited the manuscript. PK—Offered technical advice and performed part of the statistical analysis. AS—Collected histologic material, reviewed and critically edited the manuscript. XC—Performed bioinformatics analysis. Reviewed and critically edited the manuscript. KK—Offered advice on methods, interpreted part of the results, reviewed and critically edited the manuscript. MLH—Collected clinical information. Reviewed and critically edited the manuscript. CAR—Performed nucleic acid extraction, the technical part of RNA profiling and quality assurance. Reviewed and critically edited the manuscript. MAZ—Collected histologic material, reviewed and critically edited the manuscript. SHP—Conceptualized, designed and overviewed the study. Interpreted results, reviewed and critically edited the manuscript. JJG—Conceptualized, designed and overviewed the study. Interpreted results, reviewed and critically edited the manuscript.
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The study was approved by the Mayo Clinic Institutional Review Board (Application Number 18-002756).
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Chatzopoulos, K., Sotiriou, S., Collins, A.R. et al. Transcriptomic and Immunophenotypic Characterization of Tumor Immune Microenvironment in Squamous Cell Carcinoma of the Oral Tongue. Head and Neck Pathol 15, 509–522 (2021). https://doi.org/10.1007/s12105-020-01229-w
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DOI: https://doi.org/10.1007/s12105-020-01229-w