INTRODUCTION: Tissue kallikrein and the kallikrein-related peptidases (KLKs) constitute a family of 15 homologous secreted serine proteases with trypsin- or chymotrypsin-like activities, which participate in a broad spectrum of physiological procedures. Deregulated expression and/or activation of the majority of the family members have been reported in several human diseases, thereby making KLKs ideal targets for therapeutic intervention. AREAS COVERED: In the present review, we summarize the role of KLKs in normal human physiology and pathology, focusing on prostate cancer and skin diseases. Furthermore, we discuss the recent advances in the development of KLK-based therapies. A great number of diverse engineered KLKs inhibitors with improved potency, selectivity and immunogenicity have been synthesized by redesigning examples that are endogenous and naturally occurring. Moreover, encouraging results have been documented using KLKs-based vaccines and immunotherapies, as well as KLKs-mediated activation of pro-drugs. Finally, KLKs-targeting aptamers and KLKs-based imaging tools represent novel approaches towards the exploitation of KLKs' therapeutic value. EXPERT OPINION: The central/critical roles of KLK family in several human pathologies highlight KLKs as attractive molecular targets for developing novel therapeutics.

PURPOSE: Programmed death-ligand 1 (PD-L1; also known as CD274 or B7-H1) expression represents a mechanism of immune escape for cancer. Our purpose was to characterize tumor PD-L1 expression and associated T-cell infiltration in primary laryngeal squamous cell carcinomas (SCC). EXPERIMENTAL DESIGN: A well-annotated cohort of 260 operable primary laryngeal SCCs [formalin-fixed paraffin-embedded (FFPE) specimens] was morphologically characterized for stromal tumor-infiltrating lymphocytes (TIL), on hematoxylin/eosin-stained whole sections and for PD-L1 mRNA expression by qRT-PCR in FFPE specimens. For PD-L1 protein expression, automated quantitative protein analysis (AQUA) was applied on tissue microarrays consisting of two cores from these tumors. In addition, PD-L1 mRNA expression in fresh-frozen tumors and normal adjacent tissue specimens was assessed in a second independent cohort of 89 patients with primary laryngeal SCC. RESULTS: PD-L1 mRNA levels were upregulated in tumors compared with surrounding normal tissue (P = 0.009). TILs density correlated with tumor PD-L1 AQUA levels (P = 0.021). Both high TILs density and high PD-L1 AQUA levels were significantly associated with superior disease-free survival (DFS; TILs: P = 0.009 and PD-L1: P = 0.044) and overall survival (OS; TILs: P = 0.015 and PD-L1: P = 0.059) of the patients and retained significance in multivariate analysis. CONCLUSIONS: Increased TILs density and PD-L1 levels are associated with better outcome in laryngeal squamous cell cancer. Assessment of TILs and PD-L1 expression could be useful to predict response to immune checkpoint inhibitors.