Failure to respond to anti-Programmed Death receptor-1 (PD-1) treatment has been linked to high levels of transforming growth factor (TGF)-β in the tumor microenvironment (TME). Since TGF-β requires activation to be functional, we evaluated the expression of the receptor glycoprotein-A repetition predominant (GARP), which facilitates TGF-β activation, on oral squamous cell carcinoma (OSCC) surgical resections.
Immunohistochemistry (IHC) for GARP and CD45 was performed on sixty-eight FFPE OSCC resection specimens. Presence (negative vs. positive) and expression pattern (diffuse or marginal) were determined. Expression patterns were linked to patient overall survival. Gene expression profiling was performed, using a Tumor-signaling (TS)360 panel, on RNA isolated from GARP negative, -diffuse and –marginal OSCC specimens (n=4 each), matched for clinicopathological features.
We observed poor clinical outcome when OSCC expressed GARP on the outer rim of tumor islands located at the invasive tumor border (marginal localization) compared to tumors that lacked GARP expression or diffusely expressed GARP throughout the tumor. Gene expression analysis revealed that GARP-marginal tumors beside expressing more TGF-β1 and GARP, had enhanced expression of genes regulating “tumor-promoting inflammation”, “NF-κB signaling” and “Epithelial-to-Mesenchymal transition”. Based on the expression data, GARP-marginal tumors displayed increased CD45 immune cell infiltration, with myeloid cells having the most abundant cell scores. Quantifying CD45 in consecutive sections from GARP IHC revealed that while CD45 was present in the TME of GARP-marginal tumors in similar levels as GARP-negative tumors, significantly fewer CD45+ cells were able to penetrate GARP-marginal tumor islands compared to GARP-negative tumor islands within the same tumor specimen.
Our data suggest that infiltrating oral cancers utilize the GARP/TGF-β axis to support a pro-tumor TME and exclude infiltration of immune cells within tumor fields.
The authors.
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All authors have declared no conflicts of interest.