The Evolving Landscape of PD-1/PD-L1 Pathway in Head and Neck Cancer

Abstract

Over the past 10 years, cancer immunotherapy has made significant progress in multiple cancer types and has been gradually been applied to clinical cancer care, in which the programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is one of the most attractive targets. Compared with traditional therapies, the emerging PD-1/PD-L1 blockade immunotherapy exhibited more satisfactory curative effects and lower toxicity for patients with advanced head and neck squamous cell carcinoma (HNSCC). This review analyzes the expression characteristics and clinical significance of PD-1/PD-L1 in HNSCC, the immunosuppressive roles of tumor cell and stromal cell expressing PD-1/PD-L1 in this disease, and presents the development landscape of PD-1/PD-L1 inhibitors, which may provide new curative alternatives for recurrent or metastatic HNSCC.

Keywords: PD-1; PD-L1; head and neck; immunotherapy; prognostic.

Figure 1

This figure shows the immunosuppressive microenvironment mediated by PD-1/PD-L1 pathway. CAF, Cancer-associated fibroblasts; TAM, Tumor-associated macrophages; Treg, regulatory T cells. (A) PD-L1 on tumor cells combines with PD-1 on cytotoxic T cells transmits an inhibitory second signal to T cells, causing effector T cells exhaustion, dysfunction and tumor progression. At the same time, PD-L1 can act as a ligand to bind with CD80 on effector T cells, competitively inhibits the binding of costimulatory molecule CD28 with CD80, and hinders T cell activation. (B) PD-L1 also binds to PD-1 on Tregs, resulting in immune suppression by raising the threshold for T-cell activation. (C) For NK cells, PD-1 represents an “activated” phenotype and binds to PD-L1 on tumor cells or stromal cells, leading to its dysfunction. (D) Activation of PD-1 signals on B cells can inhibit the proliferation of CD4⁺ and CD8 T⁺ cells. (E) Activated CD4⁺ T helper cells modulated the up-regulation of PD-L1 expression on macrophages via IFN-γ, and TAMs could mediate adaptive resistance and dampen tumor specific T cell function based on PD-L1 expression. (F) HNSCC tumor cells recruit fibroblasts and up-regulate PD-L1 expression on fibroblasts. Conversely, fibroblasts can increase PD-L1 expression on HNSCC cells. (G) PD-L1 on tumor cells binding with PD-1 can transmit anti-apoptotic signals to the tumor themselves. (H) PD-1 antibodies can competitively inhibit the binding of PD-1 to PD-L1, while PD-L1 antibodies bind to PD-1, and they both inhibit the activation of the PD-1/PD-L1 signal pathway and reverse the suppressive effect.