conducted a phase III trial KEYNOTE-048 in which 882 patients were enrolling, comparing the curative effect of pembrolizumab or pembrolizumab combined with chemotherapy (P + C) vs. oropharynx, and hypopharynx)Ou et al. (47)381% on both tumor and immune cells 5% on both tumor and immune cells71.1% 50%No significant relationshipHNSCC (multiple sites) Open in a separate window With HPV infection becoming a cause of a subset of HNSCC, of which the incidence is increasing year by year, many studies intent on finding out how the immune microenvironment of HPV-positive tumors is different from HPV-negative tumors, including the expression differences of PD-L1. Although few studies found no correlation between PD-L1 and HPV positivity (46, 47), most have indicated that PD-L1 expression levels are positively related to HPV infection (33, 44, 48C50). Moreover, a meta-analysis RN-1 2HCl showed that PD-L1 positive expression accounted for 42% of 3,105 HNSCC patients and was associated with HPV status (51). These results suggest that PD-1/PD-L1 pathway RN-1 2HCl plays a specific role in the pathogenesis and development of HPV-positive HNSCC. Biological Significance and Prognosis Value of PD-1/PD-L1 Axis in HNSCC Since the PD-1/PD-L1 pathway is involved in immune evasion and tumor progression, many researchers have conducted in-depth research into whether the expression level of PD-1 and PD-L1 protein in tumor tissues is related to the clinical characteristics and biological behavior of HNSCC. However, the current results are still controversial. Some researchers concluded that stronger PD-L1 immunostaining in HNSCC tissues correlates with distant metastases and worse outcomes, independent of tumor origin (52). Similarly, Moratin et al. found that higher PD-L1 expression in OSCC was associated significantly with tumor size, clinical stage, regional metastases, as well as worse overall survival (OS) (53). Additionally, levels of PD-L1 that carried by circulating exosomes were positively correlated with the UICC stage and the lymph node status of HNSCC, indicating that PD-L1 expression in circulating exosomes may also be a metric for HNSCC (26). On the contrary, others reported that higher PD-1/PD-L1 expression predicted a better outcome, with significantly fewer local and distant recurrences which was particularly prominent in HPV-positive patients (48, 54). In a study of tonsillar cancer, patients with both HPV and PD-L1 positivity had longer Rabbit polyclonal to TDGF1 progression-free survival (PFS), OS, and lower risk of death (49). It was reported that HPV-positive HNSCC patients had high PD-1 expression, and the PD-1 high group in these patients who treated with radiotherapy had better recurrence-free survival (55). And the therapeutic response to immunotherapy was better in HNSCC patients with higher PD-L1 expression (56). Thus, the better outcome of PD-1-PD-L1+ HNSCC patients may be a result of better response to radiotherapy and immunotherapy. However, Kim et al. reported that PD-L1 expression of tumor cells is not related to the clinical characteristics and prognosis RN-1 2HCl of HNSCC patients (46). HNSCC patients whose tumor cells do not express PD-L1 still respond to treatment, which demonstrates that PD-L1 or PD-1 expression on non-tumor cells plays a specific role. A meta-analysis of PD-L1 expression detected by IHC in predicting survival of HNSCC patients suggested no significant difference in OS between PD-L1-positive and -negative HNSCC patients (51). While for patients with low CD8+ tumor-infiltrating T cells, a poorer OS was detected in those with positive PD-L1 expression than those with negative PD-L1 expression, showing that PD-L1 expression on immune cells rather than tumor cells was associated with a better outcome for HNSCC (51, 57). In a study of nasopharyngeal cancer, PD-1 expression was higher in CD8+ TILs than that in healthy tissues and correlated with poor prognosis (58). These indicated that PD-L1 or PD-1 expression on non-tumor cells may be useful for guiding treatment of HNSCC and the prognostic role of PD-L1 expression combined with immune cells infiltrating should be further investigated. HPV infection can affect the host immune response and immune activation in HNSCC. Recent research has found that HPV-positive HNSCC showed a higher level of PD-1 mRNA and.