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PD-1 blockade delays tumor growth by inhibiting an intrinsic SHP2/Ras/MAPK signalling in thyroid cancer cells.
Liotti, Federica; Kumar, Narender; Prevete, Nella; Marotta, Maria; Sorriento, Daniela; Ieranò, Caterina; Ronchi, Andrea; Marino, Federica Zito; Moretti, Sonia; Colella, Renato; Puxeddu, Efiso; Paladino, Simona; Kano, Yoshihito; Ohh, Michael; Scala, Stefania; Melillo, Rosa Marina.
Afiliação
  • Liotti F; Institute of Experimental Endocrinology and Oncology (IEOS), CNR, Naples, Italy.
  • Kumar N; Institute of Experimental Endocrinology and Oncology (IEOS), CNR, Naples, Italy.
  • Prevete N; Institute of Experimental Endocrinology and Oncology (IEOS), CNR, Naples, Italy.
  • Marotta M; Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
  • Sorriento D; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy.
  • Ieranò C; Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.
  • Ronchi A; Functional Genomics, Istituto Nazionale Tumouri "Fondazione G. Pascale", IRCCS, Naples, Italy.
  • Marino FZ; Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
  • Moretti S; Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
  • Colella R; Department of Medicine, University of Perugia, Perugia, Italy.
  • Puxeddu E; Department of Experimental Medicine, University of Perugia, Perugia, Italy.
  • Paladino S; Department of Medicine, University of Perugia, Perugia, Italy.
  • Kano Y; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy.
  • Ohh M; Department of Clinical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
  • Scala S; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
  • Melillo RM; Department of Biochemistry Faculty of Medicine, University of Toronto, Toronto, Canada.
J Exp Clin Cancer Res ; 40(1): 22, 2021 Jan 07.
Article em En | MEDLINE | ID: mdl-33413561
ABSTRACT

BACKGROUND:

The programmed cell death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 are immune checkpoints that suppress anti-cancer immunity. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their activity. Recently, PD-1 expression has also been found in cancer cells. Here, we analysed expression and functions of PD-1 in thyroid cancer (TC).

METHODS:

PD-1 expression was evaluated by immunohistochemistry on human TC samples and by RT-PCR, western blot and FACS on TC cell lines. Proliferation and migration of TC cells in culture were assessed by BrdU incorporation and Boyden chamber assays. Biochemical studies were performed by western blot, immunoprecipitation, pull-down and phosphatase assays. TC cell tumorigenicity was assessed by xenotransplants in nude mice.

RESULTS:

Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 was also constitutively expressed on TC cell lines. PD-1 overexpression/stimulation promoted TC cell proliferation and migration. Accordingly, PD-1 genetic/pharmacologic inhibition caused the opposite effects. Mechanistically, PD-1 recruited the SHP2 phosphatase to the plasma membrane and potentiated its phosphatase activity. SHP2 enhanced Ras activation by dephosphorylating its inhibitory tyrosine 32, thus triggering the MAPK cascade. SHP2, BRAF and MEK were necessary for PD-1-mediated biologic functions. PD-1 inhibition decreased, while PD-1 enforced expression facilitated, TC cell xenograft growth in mice by affecting tumour cell proliferation.

CONCLUSIONS:

PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the SHP2/Ras/MAPK signalling pathway.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Glândula Tireoide / Quinases de Proteína Quinase Ativadas por Mitógeno / Inibidores de Checkpoint Imunológico Limite: Humans Idioma: En Revista: J Exp Clin Cancer Res Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Itália

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Glândula Tireoide / Quinases de Proteína Quinase Ativadas por Mitógeno / Inibidores de Checkpoint Imunológico Limite: Humans Idioma: En Revista: J Exp Clin Cancer Res Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Itália