Abstract
The expression of PD-L1 by tumor cells is mainly associated with its immunosuppressive effect. In fact, PD-1/PD-L1 immune checkpoint inhibitors demonstrated remarkable effects in advanced cancer patients including HNSCC. In this context, irradiation is currently being investigated as a synergistic treatment modality to immunotherapy. However, the majority of HNSCC patients still show little improvement or even hyperprogression. Interestingly, there is increasing evidence for additional cell-intrinsic functions of PD-L1 in tumor cells. In previous studies, we showed that PD-L1 has a strong influence on proliferation, migration, invasion, and survival after irradiation. We demonstrated that cellular expression and localization of PD-L1 differed depending on sensitivity to irradiation. Here, we show that PD-L1 is also differentially expressed during cell cycle progression of HNSCC. Furthermore, cellular localization of PD-L1 also changes depending on a particular cell cycle phase. Moreover, distinct observations occurred depending on the general differentiation status. Overall, the function of PD-L1 cannot be generalized. Rather, it depends on the differentiation status and microenvironment. PD-L1 expression and localization are variable, depending on different factors. These findings may provide insight into why differential response to PD-1/PD-L1 antibody therapy can occur. Detailed understanding of cell-intrinsic PD-L1 functions will further allow antibody-based immunotherapy to be optimized.
Highlights
Head and neck squamous cell carcinoma (HNSCC) represents the eighth most common cancer worldwide
To determine whether PD-L1 itself has an impact on cell cycle progression, we reduced PD-L1 expression via small interfering RNA (siRNA) knockdown and subsequently quantified the proportion of cells in distinct cell cycle phases via FACS analysis
HNSCC tumors produce many neoantigens and, if HPV infection is involved, they are potentially targeted by T cells due to the viral antigen expression thereby provoking an immune response [27]
Summary
Head and neck squamous cell carcinoma (HNSCC) represents the eighth most common cancer worldwide. Despite remarkable progress over the last decades, the 5 year overall survival rate of patients with HNSCC is still approximately 50% [2]. The PD-1/PD-L1 immune checkpoint plays a critical role in regulating T-cell activity during the inflammatory response to infection and controlling autoimmunity [3]. Studies show that cancer cells expressing PD-L1 can evade the immune response. Immune checkpoint inhibition has shown promising results, a substantial number of patients still show little improvement or even hyperprogression after treatment with PD-1/PD-L1 antibodies. Many cancer patients fail to respond to anti-PD-1/PD-L1 treatment, and the underlying mechanisms are not well understood [12,13]. Heterogeneity of PD-L1 expression is common and accounts, to some extent, for some non-predictable results of PD-L1 status [14]
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