Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.

Adaptor Proteins, Signal Transducing / chemistry Adenocarcinoma / drug therapy Allografts / immunology Amino Acid Motifs Animals Apoptosis / drug effects B7-H1 Antigen / metabolism Cancer-Associated Fibroblasts / metabolism Carcinoma, Pancreatic Ductal / drug therapy Cell Line, Tumor Cell Membrane / drug effects Deoxycytidine / analogs & derivatives Drug Synergism Endocytosis / drug effects Equilibrative Nucleoside Transporter 1 / metabolism Humans Immunosuppression Therapy Immunotherapy Lysosomes / drug effects Mice Microfilament Proteins / chemistry Molecular Targeted Therapy NIMA-Interacting Peptidylprolyl Isomerase / metabolism Oncogenes Organoids / drug effects Pancreatic Neoplasms / drug therapy Signal Transduction / drug effects Survival Analysis Tumor Microenvironment / drug effects Xenograft Model Antitumor Assays Gemcitabine
Pin1 cancer immune evasion cancer-associated fibroblasts chemotherapy combination therapy immuni checkpoint therapy pancreatic cancer targeted therapy tumor immune microenvironment tumor microenvironment

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
02 09 2021
Historique:
received: 16 09 2020
revised: 21 04 2021
accepted: 15 07 2021
pubmed: 14 8 2021
medline: 5 1 2022
entrez: 13 8 2021
Statut: ppublish

Résumé

Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissions of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse model systems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME by acting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and the gemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways. Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts the desmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, rendering PDAC eradicable by immunochemotherapy.

Identifiants

DOI: 10.1016/j.cell.2021.07.020 PMID: 34388391 PMC: PMC8557351
pubmed: 34388391
pii: S0092-8674(21)00879-5
doi: 10.1016/j.cell.2021.07.020
pmc: PMC8557351
mid: NIHMS1727830
pii:
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
B7-H1 Antigen 0
CD274 protein, human 0
Equilibrative Nucleoside Transporter 1 0
HIP1R protein, human 0
Microfilament Proteins 0
NIMA-Interacting Peptidylprolyl Isomerase 0
SLC29A1 protein, human 0
Deoxycytidine 0W860991D6
Pin1 protein, mouse EC 5.2.1.8
Gemcitabine 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

4753-4771.e27

Subventions

Organisme : NCI NIH HHS
ID : U54 CA225088
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007627
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA168504
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS096835
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA205153
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG055559
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA224193
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA226776
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES010126
Pays : United States

Commentaires et corrections

Type : CommentIn
Type : CommentIn

Informations de copyright

Copyright © 2021 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests K.K., G.M.W., T.D.M., B.J.P., N.L., N.S.G., X.Z.Z., and/or K.P.L. are inventors of a number of issued patents and/or pending patent applications on Pin1, Pin1 biomarkers, Pin1 inhibitors, and Pin1 inhibitor combination to treat human diseases; X.Z.Z. and K.P.L. are inventors of cis P-tau antibody technology, which was licensed by BIDMC to the startup Pinteon Therapeutics. X.Z.Z. and K.P.L. are the scientific founders and former scientific advisors of and own equity in Pinteon. Their interests were reviewed and are managed by BIDMC in accordance with its conflict of interest policy. G.M.W. reports research funding from Glaxo Smith Kline (institutional funding). N.S.G. is a founder, science advisory board member (SAB), and equity holder in Gatekeeper, Syros, C4, Allorion, Jengu, Inception, B2S, EoCys, Larkspur, and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield, and Sanofi. All other authors do not have any competing interests.

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Auteurs

Kazuhiro Koikawa (K)

Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Shin Kibe (S)

Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Futoshi Suizu (F)

Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.

Nobufumi Sekino (N)

Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Nami Kim (N)

Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Theresa D Manz (TD)

Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Benika J Pinch (BJ)

Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Dipikaa Akshinthala (D)

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Ana Verma (A)

Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Giorgio Gaglia (G)

Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Yutaka Nezu (Y)

Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.

Shizhong Ke (S)

Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Chenxi Qiu (C)

Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Kenoki Ohuchida (K)

Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Yoshinao Oda (Y)

Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Tae Ho Lee (TH)

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Babara Wegiel (B)

Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Division of Surgical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

John G Clohessy (JG)

Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Nir London (N)

Department of Chemical and Structural Biology, The Weizmann Institute of Science, Rehovot, 7610001, Israel.

Sandro Santagata (S)

Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Gerburg M Wulf (GM)

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Manuel Hidalgo (M)

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Senthil K Muthuswamy (SK)

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Masafumi Nakamura (M)

Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Nathanael S Gray (NS)

Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.

Xiao Zhen Zhou (XZ)

Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: xzhouenator@gmail.com.

Kun Ping Lu (KP)

Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: klu@broadinstitute.org.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Régions du corps › Transplants › Allogreffes › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structure secondaire des protéines › Motifs d'acides aminés › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Eucaryotes › Animaux › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Antigènes B7 › Antigène CD274 › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Cellules › Cellules du tissu conjonctif › Fibroblastes › Fibroblastes associés au cancer › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Carcinome du canal pancréatique › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Cellules › Structures cellulaires › Membrane cellulaire › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléosides › Nucléosides pyrimidiques › Désoxycytidine › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Interactions médicamenteuses › Synergie des médicaments › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Endocytose › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Protéines transporteurs de solutés › Transporteurs équilibrants de nucléosides › Transporteur équilibrant de nucléosides de type 1 › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Techniques d'investigation › Techniques immunologiques › Immunosuppression thérapeutique › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Thérapeutique › Biothérapie › Immunothérapie › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Vésicules cytoplasmiques › Lysosomes › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cytosquelette › Protéines des microfilaments › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Thérapie moléculaire ciblée › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Isomerases › Cis-trans-isomerases › Peptidylpropyl isomerase › NIMA-interacting peptidylprolyl isomerase › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Gènes tumoraux › Oncogènes › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Tissus › Organoïdes › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse de survie › Targeting Pin1 renders pancreatic cancer...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › Targeting Pin1 renders pancreatic cancer...
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