RESUMEN

Immunotherapy is becoming an advanced clinical management for various cancers. Rebuilding of aberrant immune surveillance on cancers has achieved notable progress in the past years by either in vivo or ex vivo engineering of efficient immune cells. Immune cells can be programmed with several strategies that improves their therapeutic influence and specificity. It has become noticeable that effective immunotherapy must consider the complete complexity of the immune cell function. However, today, almost all immune cells can be transiently or stably reprogrammed against various cancer cells. As a consequence, investigations have interrogated strategies to improve the efficacy of cancer immunotherapies by enhancing T-cell infiltration into tumour tissues. Here, we review the emerging role of furin-like enzymes work related to T-cell reprogramming, their tumour infiltration and cytotoxic function.

Asunto(s)

Furina , Neoplasias , Humanos , Furina/uso terapéutico , Inmunoterapia , Neoplasias/tratamiento farmacológico , Linfocitos T/patología , Microambiente Tumoral

RESUMEN

Proprotein convertases or PCs are known to regulate the malignant phenotype of colon cancer cells by different mechanisms, but their effects on cancer stem cells (CSCs) have been less widely investigated. Here, we report that PCs expression is altered in colon CSCs, and the inhibition of their activity reduced colon CSCs growth, survival, and invasion in three-dimensional spheroid cultures. In vivo, repression of PCs activity by the general PC inhibitors α1-PDX, Spn4A, or decanoyl-RVKR-chloromethylketone (CMK) significantly reduced tumor expression levels of the stem cell markers LGR5 and NANOG that are associated with reduced tumor xenografts. Further analysis revealed that reduced tumor growth mediated by specific silencing of the convertase Furin in KRAS or BRAF mutated-induced colon tumors was associated with reduced expression of LGR5 and NANOG compared to wild-type KRAS and BRAF tumors. Analysis of various calcium regulator molecules revealed that while the calcium-transporting ATPase 4 (ATP2B4) is downregulated in all the Furin-silenced colon cancer cells, the Ca2+-mobilizing P2Y receptors, was specifically repressed in BRAF mutated cells and ORAI1 and CACNA1H in KRAS mutated cells. Taken together, our findings indicate that PCs play an important role in the malignant phenotype of colon CSCs and stem cell markers' expression and highlight PCs repression, particularly of Furin, to target colon tumors with KRAS or BRAF mutation.