PDL1 signals through conserved sequence motifs to overcome interferon-mediated cytotoxicity
Fecha
2017Autor
Versión
Acceso abierto / Sarbide irekia
Tipo
Artículo / Artikulua
Versión
Versión publicada / Argitaratu den bertsioa
Impacto
|
10.1016/j.celrep.2017.07.075
Resumen
PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation
through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic
signaling protects cancer cells from interferon (IFN)
cytotoxicity and accelerates tumor progression.
PDL1 inhibited IFN signal transduction through a
conserved class of sequence motifs that mediate ...
[++]
PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation
through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic
signaling protects cancer cells from interferon (IFN)
cytotoxicity and accelerates tumor progression.
PDL1 inhibited IFN signal transduction through a
conserved class of sequence motifs that mediate
crosstalk with IFN signaling. Abrogation of PDL1
expression or antibody-mediated PDL1 blockade
strongly sensitized cancer cells to IFN cytotoxicity
through a STAT3/caspase-7-dependent pathway.
Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted
motif regulation, resulting in PDL1 molecules with
enhanced protective activities from type I and type
II IFN cytotoxicity. Overall, our results reveal a
mode of action of PDL1 in cancer cells as a first line
of defense against IFN cytotoxicity. [--]
Materias
PDL1,
PD-L1,
B7-H1,
CD274,
PD1,
Interferon,
Signal transduction,
Immunotherapy
Editor
Elsevier
Publicado en
Cell Reports, 2017, 20 (8), pp. 1818-1829
Departamento
Universidad Pública de Navarra. Departamento de Ciencias de la Salud /
Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila
Versión del editor
Entidades Financiadoras
This project was funded by a crowdfunding project by FECYT (PRECIPITA, Spain), an FIS grant (PI14/00579) from the Instituto de Salud Carlos III, a grant from the Government of Navarre (Spain; BMED 033-2014), and a grant from Fundación Caixa (Spain) to G.K. We thank the SARAY Foundation (Navarra, Spain) and Sandra Ibarra’s foundation for financial support. M.G. is funded by a PhD fellowship granted by the Government of Navarre. M.Z. is funded by a fellowship granted by Universidad Pública de Navarra (UPNA), Spain. M.I.V. is funded by a Sara Borrel Fellowship. I.A. is funded by a Miguel Servet Fellowship. K.B. received funding from Kom Op Tegen Kanker (Belgium). We especially thank Luciano Escors, Lucia Murugarren, and family for their donations and overall support, as well as all the donors who contributed to the ‘PRECIPITA’ project. D.E. is funded by a Miguel Servet Fellowship (CP12/03114) awarded by the Instituto de Salud Carlos III (Spain).