At the Crossroads of Molecular Biology and Immunology: Molecular Pathways for Immunological Targeting of Head and Neck Squamous Cell Carcinoma

Abstract

Background: Recent advances in immunotherapy for head and neck squamous cell carcinoma (HNSCC) have led to implementation of anti-programmed death receptor 1 (PD-1) immunotherapy to standard of care for recurrent/metastatic HNSCC. However, the majority of tumors do not respond to these therapies, indicating that these tumors are not immunogenic or other immunosuppressive mechanisms might be at play.Aim: Given their role in carcinogenesis as well as in immune modulation, we discuss the relation between the STAT3, PI3K/AKT/mTOR and Wnt signaling pathways to identify potential targets to empower the immune response against HNSCC.Results: We focused on three pathways. First, STAT3 is often overactivated in HNSCC and induces the secretion of immunosuppressive cytokines, thereby promoting recruitment of immune suppressive regulatory T cells and myeloid-derived suppressor cells to the tumor microenvironment (TME) while hampering the development of dendritic cells. Second, PI3K/AKT/mTOR mutational activation results in increased tumor proliferation but could also be important in HNSCC immune evasion due to the downregulation of components in the antigen-processing machinery. Third, canonical Wnt signaling is overactivated in >20% of HNSCC and could be an interesting pleotropic target since it is related to increased tumor cell proliferation and the development of an immunosuppressive HNSCC TME.Conclusion: The molecular pathology of HNSCC is complex and heterogeneous, varying between sites and disease etiology (i.e., HPV). The in HNSCC widely affected signaling pathways STAT3, PI3K/AKT/mTOR and Wnt are implicated in some of the very mechanisms underlying immune evasion of HNSCC, thereby representing promising targets to possibly facilitate immunotherapy response.

The Role of Immune Modulatory Cytokines in the Tumor Microenvironments of Head and Neck Squamous Cell Carcinomas

“…In HNSCCs, three pathways, STAT3, PI3K/AKT/mTOR, and Wnt, are the important signaling pathways underlying the immune evasion of HNSCCs. Therefore, targeting some molecules of these signals could contribute to facilitating immune therapies [ 130 ].…”

Immune microenvironment of human papillomavirus-positive head and neck squamous cell carcinoma

“… 62 One approach to overcome immune evasion is to target the known molecular pathways in HNSCC that are affected and associated specifically with its immune characteristics, focusing on three pathways: STAT3, PI3 K/AKT/mTOR, and Wnt pathways. 63 Recently, a study in HPV-positive HNSCC patients identified CD8+ T cell epitopes derived from the E2 immune target and detected a large number of E2-specific CD8+ T cells in the TME of such patients, demonstrating that E2 is a primary immunotherapeutic target. 64 , 65 Furthermore, the role of intracellular DNA sensor agonists in immune therapy has received increasing attention.…”

Biomarkers and 3D models predicting response to immune checkpoint blockade in head and neck cancer (Review)

“…Signaling pathways are widely affected in HNSCC and are known to be involved in processes underlying immune evasion in HNSCC. Wondergem et al ( 64 ) explored three pathways: STAT3, PI3K/AKT/mTOR and Wnt, which are assumed to represent promising targets to possibly facilitate immunotherapy response. These pathways are of particular importance, because they are involved in cellular processes considered to account for primary or acquired resistance to immunotherapy.…”

“…The aim is to stop the propagation of tumor cells and stimulate the immune response at the same time by blocking responsible signaling cascades. The emphasis should be on the comparison between HPV-driven and non-driven head and neck cancer patients as different pathways seem to be relevant for their respective immune response and response to drugs ( 64 ). Oncogenic pathways that are activated through gain-of-function alterations in oncogenes or loss-of-function alterations in tumor suppressor genes are known to influence the local anti-tumor immune response.…”