TY - CONF
T1 - Bi-directional crosstalk between NAD/NAMPT and IFN-γ/PD-L1axes in melanoma
AU - Fiorilla, Irene
AU - Todesco, Alberto Maria
AU - Ugolini, Filippo
AU - Moiso, Enrico
AU - Piraino, Rossana
AU - Baroni, Gianna
AU - de Cesaris, Barbara
AU - Szumera-Ciećkiewicz, Anna
AU - Calautti, Vincenzo
AU - Massi, Daniela
AU - AUDRITO, VALENTINA
PY - 2024
Y1 - 2024
N2 - Targeted therapy and immune checkpoint inhibitors (ICIs) have notably improved the treatment of BRAF-
mutated metastatic melanoma (MM) patients; however, resistance mechanisms dramatically impact on the
survival of patients. In MM cells resistant to the BRAF inhibitors the NAD/nicotinamide
phosphoribosyltransferase (NAMPT) axis is overactivated, thus becoming a driver of melanoma progression
and resistance. Moreover, extracellular NAMPT, released within the tumor microenvironment, acts as a
cytokine-like factor potentially regulating tumor-host interactions.
Recent studies highlighted a potential correlation between the NAD/NAMPT axis and interferon-gamma
(IFN-γ)-mediated signaling. Analyzing the TCGA melanoma cohort and cell lines database we found a
positive and significant correlation between NAMPT expression and global IFN-γ signaling, as well as a
direct correlation with IRF1, STAT1, and the IFN-γ-induced gene CD274. Focusing on CD274/PD-L1, we
revealed a direct correlation with NAMPT at protein level, as demonstrated by analyzing a melanoma tissue
microarray. BRAF-mutated melanoma cell lines treated with IFN-γ upregulate NAMPT, and vice versa,
pharmacological inhibitors of NAMPT activity markedly reduced the activation of the IFN-γ signaling, as
well as the expression of CD274/PD-L1. PD-L1, implicated in immune evasion mechanisms in tumors, is
regulated at the transcriptional level via IFN-γ/IRF1 axis, but also through the Bromodomain and Extra-
Terminal motif (BET) epigenetic factors. Our data revealed a similar molecular regulation also for NAMPT,
as demonstrated by the downregulation of NAMPT expression in the presence of JQ1 and AZD5153, two
BET protein inhibitors. This novel epigenetic regulation of NAMPT expression via BET proteins will be
further investigated.
Overall, these data highlighted a novel reciprocal regulation between NAMPT and IFN-γ/PD-L1 signaling
activation, linking NAMPT-dependent metabolic reprogramming and immune regulation.
AB - Targeted therapy and immune checkpoint inhibitors (ICIs) have notably improved the treatment of BRAF-
mutated metastatic melanoma (MM) patients; however, resistance mechanisms dramatically impact on the
survival of patients. In MM cells resistant to the BRAF inhibitors the NAD/nicotinamide
phosphoribosyltransferase (NAMPT) axis is overactivated, thus becoming a driver of melanoma progression
and resistance. Moreover, extracellular NAMPT, released within the tumor microenvironment, acts as a
cytokine-like factor potentially regulating tumor-host interactions.
Recent studies highlighted a potential correlation between the NAD/NAMPT axis and interferon-gamma
(IFN-γ)-mediated signaling. Analyzing the TCGA melanoma cohort and cell lines database we found a
positive and significant correlation between NAMPT expression and global IFN-γ signaling, as well as a
direct correlation with IRF1, STAT1, and the IFN-γ-induced gene CD274. Focusing on CD274/PD-L1, we
revealed a direct correlation with NAMPT at protein level, as demonstrated by analyzing a melanoma tissue
microarray. BRAF-mutated melanoma cell lines treated with IFN-γ upregulate NAMPT, and vice versa,
pharmacological inhibitors of NAMPT activity markedly reduced the activation of the IFN-γ signaling, as
well as the expression of CD274/PD-L1. PD-L1, implicated in immune evasion mechanisms in tumors, is
regulated at the transcriptional level via IFN-γ/IRF1 axis, but also through the Bromodomain and Extra-
Terminal motif (BET) epigenetic factors. Our data revealed a similar molecular regulation also for NAMPT,
as demonstrated by the downregulation of NAMPT expression in the presence of JQ1 and AZD5153, two
BET protein inhibitors. This novel epigenetic regulation of NAMPT expression via BET proteins will be
further investigated.
Overall, these data highlighted a novel reciprocal regulation between NAMPT and IFN-γ/PD-L1 signaling
activation, linking NAMPT-dependent metabolic reprogramming and immune regulation.
UR - https://iris.uniupo.it/handle/11579/190302
M3 - Abstract
ER -