Involvement of Neutrophils in Metastatic Evolution of Pancreatic Neuroendocrine Tumors.
Fiche publication
Date publication
juin 2021
Journal
Cancers
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BACHELLIER Philippe, Pr CHENARD Marie-Pierre, Dr DAVIDSON Irwin, Pr KURTZ Jean-Emmanuel, Pr PESSAUX Patrick, Pr MALOUF Gabriel, Pr IMPERIALE Alessio, Dr BALTZINGER Philippe
Tous les auteurs :
Debien V, Davidson G, Baltzinger P, Kurtz JE, Séverac F, Imperiale A, Pessaux P, Addeo P, Bachellier P, Su X, Davidson I, Chenard MP, Goichot B, Malouf GG
Lien Pubmed
Résumé
Well-differentiated pancreatic neuroendocrine tumors (pNET) have an unpredictable natural history. The identification of both blood and tumor immune features associated with patients' outcomes remains limited. Herein, we evaluated the best prognostic value of the neutrophils-to-lymphocyte ratio (NLR) in a cohort of 144 pNETs. The NLR ≥ 4 was associated with worse overall survival in both univariate analysis (HR = 3.53, CI95% = 1.50-8.31, = 0.004) and multivariate analysis (HR = 2.57, CI95% = 1.061-6.216, = 0.036). The presence of synchronous liver metastasis was identified as a prognostic factor in multivariate analysis (HR = 3.35, CI95% = 1.411-7.973, = 0.006). Interestingly, the absolute tumor-associated neutrophils count was higher in liver metastasis as compared to their paired primary tumor ( = 0.048). Deconvolution of immune cells from the transcriptome of 83 primary tumors and 30 liver metastases reveals enrichment for neutrophils in metastasis relative to primary tumors ( = 0.005), and this was associated with upregulation of the complement pathway (NES = 1.84, < 0.0001). Combining neutrophils signature and complement pathway genes, unsupervised clustering identified two pNETs subgroups, namely Neu-Comp1 and Neu-Comp2. Characterized by neutrophils infiltration and activation of the complement pathway, Neu-Comp1 was highly enriched for metastatic liver samples as compared to Neu-Comp2 ( < 0.0001). These data suggest the possible link between liver metastasis, complement pathway activation, and neutrophils infiltration in well-differentiated pNET and open avenues for targeting complement pathways in these tumors.
Mots clés
complement, innate immunity, neutrophils, neutrophils-to-lymphocyte ratio, pancreatic neuroendocrine tumors, transcriptome, tumor microenvironment
Référence
Cancers (Basel). 2021 Jun 2;13(11):