Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer

Abstract

Many cancer types, including head and neck cancers (HNC), express programmed death ligand 1 (PD-L1). Interaction between PD-L1 and its receptor, programmed death 1 (PD-1), inhibits the function of activated T cells and results in an immunosuppressive microenvironment, but the stimuli that induce PD-L1 expression are not well characterized. Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node to transmit tumor cell-mediated extrinsic or intrinsic signals, respectively. In this study, we investigated the mechanism by which these factors upregulate PD-L1 expression in HNC cells in the context of JAK/STAT pathway activation, Th1 inflammation, and HPV status. We found that wild type, overexpressed EGFR significantly correlated with JAK2 and PD-L1 expression in a large cohort of HNC specimens. Furthermore, PD-L1 expression was induced in an EGFR- and JAK2/STAT1-dependent manner, and specific JAK2 inhibition prevented PD-L1 upregulation in tumor cells and enhanced their immunogenicity. Collectively, our findings suggest a novel role for JAK2/STAT1 in EGFR-mediated immune evasion, and therapies targeting this signaling axis may be beneficial to block PD-L1 upregulation found in a large subset of HNC tumors.

PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer

“…It has been suggested that signal pathways such as JAK/ STAT1/IRF-1, MEK/ERK/STAT1 and PKD2 etc. were involved in the regulation of PD-L1 expression, and these pathways could initiate transcription factors including IRF-1, STAT1 or STAT3, which target the promoter of PD-L1 [33][34][35]. Meanwhile, the abnormal expression of PD-L1 in cancer cells could induce a series of cellular responses that are associated with the prevention of apoptosis, failure of chemo/radio treatment and immune clearance.…”

Programmed Death-Ligand 1 Expression, Microsatellite Instability, Epstein–Barr Virus, and Human Papillomavirus in Nasopharyngeal Carcinomas of Patients from the Philippines

“…PD-L1 staining in C5% of tumor cells was frequently used to define PD-L1 positivity in retrospective studies [4,27] as well as clinical studies on PD-1/PD-L1 blockade in other solid tumors [5,8,9]. In our cohort, when PD-L1?…”

Nivolumab in the Treatment of Refractory Recurrent and Metаstatic Head and Neck Squamous Cell Carcinoma. The Results of a Phase Iii Clinical Trial (Checkmate 141)

“…В настоящее время известно, что цетуксимаб мо-жет индуцировать иммунный противоопухолевый от-вет, а ассоциированная с ним блокада рецепторов эпидермального фактора роста приводит к снижению в опухолевых клетках экспрессии PD-L1, связанной с предшествующей гиперсекрецией интерферона γ при ПРГШ [25,26]. Таким образом, терапия цетукси-мабом может влиять на результаты лечения пациентов с рецидивами ПРГШ.…”

“…Одним из наиболее важных биологических про-цессов, способствующих прогрессированию роста опухолевых клеток, является феномен ускользания опухоли от иммунного ответа организма, связанного с экспрессией рецепторов программируемой смерти 1 (Programmed cell death 1, PD-1) [5][6][7][8].…”