S100A14: A novel negative regulator of cancer stemness and immune evasion by inhibiting STAT3‐mediated programmed death‐ligand 1 expression in colorectal cancer

Background Programmed death-ligand 1 (PD-L1) has functional roles in cancer stem-like cell (CSC) phenotypes and chemoresistance besides immune evasion. Chemotherapy is a common treatment choice for colorectal cancer (CRC) patients; however, chemoresistance limits its effectiveness of treatment. Methods We examined the role of S100A14 (SA14) in CRC by adopting PD-L1(high) subpopulations within CRC cell lines and patient tumours, by establishing PD-L1(high) chemoresistant CRC sublines through prolonged exposure to 5-fluorouracil/oxaliplatin-based chemotherapy in vitro and in vivo, and by analysing a public database. Results We identified a novel function of SA14 as a regulator of immune surveillance, major CSC phenotypes, and survival capacity under hostile microenvironments, including those harbouring chemotherapeutics, and as a prognostic biomarker in CRC. Mechanistically, SA14 inhibits PD-L1 expression by directly interacting with signal transducer and activator of transcription 3 (STAT3) and inducing its proteasome-mediated degradation. While gain-of-SA14 causes loss of PD-L1 expression and tumourigenic potential and sensitisation to chemotherapy-induced apoptosis in chemoresistant CRC cells, loss-of-SA14 causes increases in PD-L1 expression, tumourigenic potential, and chemoresistance in vitro and in vivo. We further show that a combinatorial treatment with chemotherapy and recombinant SA14 protein effectively induces apoptosis in PD-L1(high) chemoresistant CRC cells. Conclusions Our results suggest that SA14-based therapy is an effective strategy to prevent tumour progression and that SA14 is a predictive biomarker for anti-PD-L1 immunotherapy and chemotherapy in combination.