STRATIfiCATION OF HEAD AND NECK SQUAMOUS CELL CARCINOMA USING COMBINED ANALYSIS OF PROGRAMMED DEATH LIGAND 1 AND SEMAPHORIN 4D EXPRESSION BY THE INflAMMATORY CELLS IN THE TUMOR MICROENVIRONMENT

Objective Inhibition of the immune check point PD-1/PD-L1 has shown unprecedented improvement in overall survival of platinum resistant head and neck squamous cell carcinoma (HNSCC) patients. PD-L1 immunohistochemical diagnostics showed to be more prognostic of the patient response. Yet, patients’ response remains limited to 45% out of the PD-L1 positive cases, where PD-L1 can be expressed by the tumor cells or by the tumor associated inflammatory cells (TAIs). Semaphorin 4D (Sema4D) is an immune modulator molecule expressed by several inflammatory cells, as well as several tumor cell types including HNSCC. We have recently described a HNSCC stratification model based on combined analysis of PD-L1/ Sema4D IHC expression by the tumor cells. Here we would like to extend our analysis to further stratify HNSCC according to Sema4D/ PD-L1 expression by TAIs in the tumor micro-environment. Findings IHC analysis of Sema4D/PD-L1 in 136 HNSCC tissue cores showed: 61% (83 cases) to be Sema4D +ve in TAIs, and 29% (39 cases) to be PD-L1 +ve TAIs. Accordingly, we were able to stratify the examined HNSCC cores into 4 subtypes using the expression of Sema4D/PD-L1 by TAIs in the tumor micro-environment: (1) Sema4D only positive (37%) (50 cases), (2) PD-L1 only positive (4%) (6 cases), (3) Sema4D/PD-L1 (+ve/+ve) (24%) (33 cases), and (4) 35% (47 cases) to be (-ve/-ve). Sema4D only +ve TAIs were significantly higher than PD-L1 only +ve TAIs. Conclusion HNSCC stratification according to Sema4D/PD-L1 expression by TAIs in the tumor microenvironment can open new avenues for personalized targeted therapy and might interpret resistance or cytotoxic effects to PD-1/PD-L1 inhibition in HNSCC.