NTSR1 abnormal expression by cancer cells makes it a strategic target for antitumoral therapies, such as compounds that use NTSR1 binding probes to deliver cytotoxic agents to tumor cells. Success of these therapies relies on NTSR1 protein availability and accessibility; therefore, understanding the protein’s biology is crucial. We studied NTSR1 protein in exogenously and endogenously expressing non-tumoral and tumoral cells. We found NTSR1 to be expressed as three distinct protein forms: the NTSR1-high form, a glycosylated protein; the NTSR1-low form, a N-terminally cleaved and de-glycosylated protein; and the NTSR1-LP protein with the MW size predicted by its NTSR1 amino acid sequence. We show that the NTSR1-high form is cleaved by MMPs to generate the NTSR1-low form, a process that is promoted by the Neurotensin (NTS) ligand. In addition, NTS induced the internalization of plasma membrane localized NTSR1 and degradation of NTSR1-low form via the proteasome. Importantly, we found NTSR1-low form to be the most abundant form in the tumoral cells and in PDAC Patient Derived Xenograft, demonstrating its physiopathological relevance. Altogether, our work provides important technical and experimental tools as well as new crucial insights into NTSR1 protein biology that are required to develop clinically relevant NTSR1 targeting anti-tumoral therapies.

Tyrosine kinase inhibitor cabozantinib impacts dendritic and natural killer cells immune response in C38 syngeneic tumor modelCabozantinib is a tyrosine kinase inhibitor approved for use in all patients with metastatic renal cell carcinoma (mRCC). Its main target is VEGFR-2 conferring its strong anti-angiogenetic properties. Beside its role in aberrant angiogenesis during tumor growth, VEGF has also been described to be implicated in the accumulation of myeloid-derived suppressor cells (MDSC) in the tumor [1]. In line with this, cabozantinib treatment reduced MDSC in murine models of prostate and penile cancer, which resulted in a boost of immune checkpoint blockade efficacy [2,3]. In humans, the combination of nivolumab and cabozantinib increased overall survival and progression-free survival of mRCC patients [4], which led to the approval of this combination as first-line therapy. As proposed by others [5], the mechanism of action of this combination could be that cabozantinib reduces immunosuppressive MDSC, while immune checkpoint blockade prevents the effect of co-inhibitory molecules expressed by tumor cells. Nevertheless, cabozantinib immune-related effects might not be limited to MDSC reduction as this tyrosine kinase inhibitor displays activity against other kinases such as MERTK, AXL, c-MET, or c-KIT, which are expressed by a variety of immunes cells. In order to identify new targets and mechanisms of action of this molecule, we investigated the effect of cabozantinib monotherapy on the antitumor immune response against the C38 murine tumor, a model poorly infiltrated by MDSC.T-cell anti-tumor response was not affected by cabozantinib as the proportion and the maturation status of these cells in the tumor and the tumor draining LN