RT Journal Article
SR Electronic
T1 Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) neutralization counteracts T cell immune evasion in breast cancer
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e007010
DO 10.1136/jitc-2023-007010
VO 11
IS 10
A1 Travelli, Cristina
A1 Colombo, Giorgia
A1 Aliotta, Martina
A1 Fagiani, Francesca
A1 Fava, Natalia
A1 De Sanctis, Rita
A1 Grolla, Ambra A
A1 Garcia, Joe G N
A1 Clemente, Nausicaa
A1 Portararo, Paola
A1 Costanza, Massimo
A1 Condorelli, Fabrizio
A1 Colombo, Mario Paolo
A1 Sangaletti, Sabina
A1 Genazzani, Armando A
YR 2023
UL http://jitc.bmj.com/content/11/10/e007010.abstract
AB Background Nicotinamide phosphoribosyltransferase (NAMPT) is a key intracellular enzyme that participates in nicotinamide adenine dinucleotide (NAD) homeostasis as well as a released cytokine (eNAMPT) that is elevated in inflammatory conditions and in cancer. In patients with breast cancer, circulating eNAMPT is elevated and its plasma levels correlate with prognosis and staging. In light of this, we investigated the contribution of eNAMPT in triple negative mammary carcinoma progression by investigating the effect of its neutralization via a specific neutralizing monoclonal antibody (C269).Methods We used female BALB/c mice injected with 4T1 clone 5 cells and female C57BL6 injected with EO771 cells, evaluating tumoral size, spleen weight and number of metastases. We injected two times a week the anti-eNAMPT neutralizing antibody and we sacrificed the mice after 28 days. Harvested tumors were analyzed by histopathology, flow cytometry, western blot, immunohistochemistry, immunofluorescence and RNA sequencing to define tumor characteristics (isolating tumor infiltrating lymphocytes and tumoral cells) and to investigate the molecular mechanisms behind the observed phenotype. Moreover, we dissected the functional relationship between T cells and tumoral cells using three-dimensional (3D) co-cultures.Results The neutralization of eNAMPT with C269 led to decreased tumor size and reduced number of lung metastases. RNA sequencing and functional assays showed that eNAMPT controlled T-cell response via the programmed death-ligand 1/programmed cell death protein 1 (PD-L1/PD-1) axis and its neutralization led to a restoration of antitumoral immune responses. In particular, eNAMPT neutralization was able to activate CD8+IFNγ+GrzB+ T cells, reducing the immunosuppressive phenotype of T regulatory cells.Conclusions These studies indicate for the first time eNAMPT as a novel immunotherapeutic target for triple negative breast cancer.Data are available upon reasonable request. The RNAseq data have been deposited in the Gene Expression Omnibus (GEO) database under the accession GSE223539.