The histological stromal inflammatory subtypes and its transcriptional immune signature defined in oral squamous cell carcinoma with the soluble Semaphorin 4D immune biomarker

Oral squamous cell carcinoma (OSCC) is a disfiguring malignancy that occurs in close proximity to vital structures, sometimes with limited treatment options. Thus, the recent immunotherapy treatment is a promising alternative. The peri-tumoral stromal inflammatory profile (PTSIP) has shown to be an important factor in determining patient's response to immunotherapy. Soluble biomarkers are a promising tool that can monitor the status of PTSIP and serve as a diagnostic method of the histological inflammatory stromal (HIS) subtypes. Semaphorin 4D (Sema4D) is a soluble immune biomarker that we previously detected in OSCC patient's plasma. The objective of this work is to define the HIS subtypes in OSCC according to the status of the PTSIP and assess the diagnostic potential of the soluble Sema4D (sSema4D) in peripheral blood, to identify OSCC HIS subtypes.

Findings

According to University of Maryland institutional review board approval, in a cohort of eighty excisional OSCC tumor tissue biopsies, we described the three HIS subtypes; inflamed (hot), the immune excluded and the de- serted (cold). Immune focused gene expression analysis of the IFN-γ signature using representative tumor samples of the three HIS subtypes was described. We also analyzed sSema4D in plasma of the same eighty OSCC patients, using healthy donors and chronic inflammation/ autoimmune/ allergy patients as controls. High sSema4D levels (HsS4D) in plasma of OSCC correlated directly with the immune excluded HIS subtype (p=0.0001). HsS4D in blood clustered with low IFN-γ tumor immune signature (TIS).

Conclusions

Our data demonstrates the histological inflammatory subtypes and the corresponding transcriptional immune signature in OSCC. It highlights sSema4D as an immune biomarker that can be diagnostic of the tumor stromal inflammation. These findings open new avenues for advancing personalized immunotherapy in OSCC.