Deciphering molecular consequences of the prohormone convertase 1/3 inhibition in macrophages for application in immunotherapy - Secretomes

ABSTRACT: The prohormone convertase 1/3 (PC1/3) is an enzyme playing an important role in the processing of precursor proteins involved in neuroimmune phenotype of neuroendocrine cells. The expression of PC1/3 is not only restricted to neuroendocrine tissues; recent studies reported a role of PC1/3 in Toll-like receptor immune response in macrophages. Here, using lentivirus strategy, we investigated the consequences of PC1/3 down-regulation with the aim of understanding the intracellular impact of such inhibition and its biological application to cancer therapy. Under sterile conditions, we demonstrated that PC1/3 inactivated macrophages express a M1-like phenotype characterized by filopodia extensions, pro-inflammatory chemokines and cytokines secretion (IL6, CXCL10; TNF) and TLR4 Myd88 dependent signaling activation. Under LPS challenge, PC1/3 KO cells secrete through store-operated calcium entry increase, a cocktail of pro-inflammatory factors including alarmins and chemokines conducting to attract naïve T helper lymphocytes (Th0) which favors cytotoxic response. Tests perform with the secreted factors by the challenged PC1/3 KO cells on breast and ovarian cancer cells (SKBR3, SKOV3) establish that the factors secreted are able to inhibit both viability and resistance to chemotherapies. Under inhibitory conditions using IL-10, the PC1/3 KO cells still continue to produce inflammatory cytokines and anti-tumoral factors. Taken together, these data establish that inhibition of PC1/3 can be used as a potential immune therapy for awaking intra-tumoral macrophages.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Cell Culture, Macrophage

SUBMITTER: Maxence Wisztorski  

LAB HEAD: Michel Salzet

PROVIDER: PXD001986 | Pride | 2015-09-15

REPOSITORIES: Pride