RESUMEN
Drug resistance and cancer relapse represent significant therapeutic challenges after chemotherapy or immunotherapy, and a major limiting factor for long-term cancer survival. Netrin-1 was initially identified as a neuronal navigation cue but has more recently emerged as an interesting target for cancer therapy, which is currently clinically investigated. We show here that netrin-1 is an independent prognostic marker for clinical progression of breast and ovary cancers. Cancer stem cells (CSCs)/Tumor initiating cells (TICs) are hypothesized to be involved in clinical progression, tumor relapse and resistance. We found a significant correlation between netrin-1 expression and cancer stem cell (CSC) markers levels. We also show in different mice models of resistance to chemotherapies that netrin-1 interference using a therapeutic netrin-1 blocking antibody alleviates resistance to chemotherapy and triggers an efficient delay in tumor relapse and this effect is associated with CSCs loss. We also demonstrate that netrin-1 interference limits tumor resistance to immune checkpoint inhibitor and provide evidence linking this enhanced anti-tumor efficacy to a decreased recruitment of a subtype of myeloid-derived suppressor cells (MDSCs) called polymorphonuclear (PMN)-MDSCs. We have functionally demonstrated that these immune cells promote CSCs features and, consequently, resistance to anti-cancer treatments. Together, these data support the view of both a direct and indirect contribution of netrin-1 to cancer stemness and we propose that this may lead to therapeutic opportunities by combining conventional chemotherapies and immunotherapies with netrin-1 interfering drugs.
RESUMEN
BACKGROUND: For patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), surgery (S) followed by radiotherapy (RT) is a standard of care. Randomized controlled trials have shown that postoperative chemoradiation (CRT) increased the locoregional control (LRC) and overall survival (OS) in patient with R1-resection margin and/or extranodal extension (ENE). ENE has been introduced in the 8th TNM staging classification since its presence has been shown to have an independent adverse prognostic impact. The data supporting this finding were however mainly collected in the pre-CRT era. OBJECTIVES: The objective of this study was to challenge the adverse prognostic factor of ENE in the era of CRT. METHODS: A retrospective cohort study was performed to evaluate patients diagnosed with LAHNSCC and undergoing a treatment by S and postoperative RT or CRT in Centre Léon Bérard, Lyon, France between 2003 and 2018. Patients with oral cavity, oropharyngeal, laryngeal and hypopharyngeal SCC were included. RESULTS: 439 patients were included in the study. For patients with non-oropharyngeal p16-positive tumors without ENE, five-year OS, local control, and regional control (RC) reached 63.7%, 86.1%, and 94.9%, respectively; corresponding figures for patients with ENE reached, 42.6%, 77.5%, and 81.1%, respectively (p-value of 0.0006, 0.167, and 0.0005). In multivariable analysis, for non-oropharyngeal p16-positive tumors, ENE remained a poor prognostic factor for OS (RR = 1.74, 95%, CI = 1.16-2.61, p = 0.0069) and RC (RR 3.60, 95% CI =: 1.64-7.87, p = 0.0013). CONCLUSION: In the era or postoperative chemoradiation, pathological ENE remains an adverse prognostic factor for OS and RC.
