Tumor Microenvironment, HLA Class I and APM Expression in HPV-Negative Oral Squamous Cell Carcinoma

SIMPLE SUMMARY: Oral squamous cell carcinoma has developed different strategies to escape from T-cell-mediated immune surveillance, which is mediated by changes in the composition of cellular and soluble components of the tumor microenvironment as well as an impaired expression of molecules of the antigen processing machinery leading to a downregulation of HLA class I surface antigens. In depth characterization of these escape mechanisms might help to develop strategies to overcome this tolerance. In this study, human papilloma virus negative oral squamous cell carcinoma lesions were analyzed regarding the protein expression of major components of the HLA class I antigen processing/presentation pathway in correlation to the intra-tumoral immune cell composition, IFN-γ signaling and clinical parameters, which was further confirmed by bioinformatics analyses of datasets obtained from The Cancer Genome Atlas. This novel knowledge could be used for optimizing the design of immunotherapeutic approaches of this disease. ABSTRACT: Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study, the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN-γ signaling and to the patient’s outcome. A heterogeneous but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells. Tumoral HLA-I APM component expression was further categorized into the three major phenotypes HLA-I(high)/APM(high), HLA-I(low)/APM(low) and HLA-I(discordant high/low)/APM(high). In the HLA-I(high)/APM(high) group, the highest frequency of intra-tumoral CD8(+) T cells and lowest number of CD8(+) T cells close to FoxP3(+) cells were found. Patients within this group presented the most unfavorable survival, which was significantly evident in stage T2 tumors. Despite a correlation with the number of intra-tumoral CD8(+) T cells, tumoral JAK1 expression as a surrogate marker for IFN-γ signaling was not associated with HLA-I/APM expression. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.