Simultaneous targeting of PD-1 and IL-2Rβγ with radiation therapy inhibits pancreatic cancer growth and metastasis.

Humans CD8-Positive T-Lymphocytes Programmed Cell Death 1 Receptor Interleukin-2 Receptor alpha Subunit / therapeutic use Interleukin-2 / pharmacology Pancreatic Neoplasms / genetics Carcinoma, Pancreatic Ductal / genetics Immunotherapy Pancreatic Neoplasms

NK cells T cell stemness Tregs antigen specificity cancer immunotherapy cytotoxic T lymphocyte immune memory metabolomics metastasis tumor immunology

Journal

Cancer cell

ISSN: 1878-3686

Titre abrégé: Cancer Cell

Pays: United States

ID NLM: 101130617

Informations de publication

Date de publication:
08 05 2023

Historique:

received: 26 09 2022

revised: 05 01 2023

accepted: 31 03 2023

pmc-release: 08 05 2024

medline: 11 5 2023

pubmed: 29 4 2023

entrez: 28 4 2023

Statut: ppublish

Résumé

In pancreatic ductal adenocarcinoma (PDAC) patients, we show that response to radiation therapy (RT) is characterized by increased IL-2Rβ and IL-2Rγ along with decreased IL-2Rα expression. The bispecific PD1-IL2v is a PD-1-targeted IL-2 variant (IL-2v) immunocytokine with engineered IL-2 cis targeted to PD-1 and abolished IL-2Rα binding, which enhances tumor-antigen-specific T cell activation while reducing regulatory T cell (Treg) suppression. Using PD1-IL2v in orthotopic PDAC KPC-driven tumor models, we show marked improvement in local and metastatic survival, along with a profound increase in tumor-infiltrating CD8

Identifiants

DOI: 10.1016/j.ccell.2023.04.001 PMID: 37116489 PMC: PMC10246400

pubmed: 37116489

pii: S1535-6108(23)00117-4

doi: 10.1016/j.ccell.2023.04.001

pmc: PMC10246400

mid: NIHMS1898030

pii:

doi:

Substances chimiques

Programmed Cell Death 1 Receptor 0

Interleukin-2 Receptor alpha Subunit 0

Interleukin-2 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

Pagination

950-969.e6

Subventions

Organisme : NCI NIH HHS

ID : P30 CA046934

Pays : United States

Organisme : NIH HHS

ID : S10 OD027023

Pays : United States

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of interests S.D.K. receives funding from the NIDCR/NCI (R01 DE028528-01; R01 DE028282-01; 1 P50 CA261605-01).S.D.K. receives clinical funding from AstraZeneca, Genentech, and Ionis that does not relate to this work. S.D.K. also receives preclinical research funding from Roche for work related to the aCD25 and PD1-IL2v antibodies used as immunotherapy in this article. A.D. is a founder of Omix Technologies, Inc., and Altis Biosciences. A.D. is a scientific advisory board member for Hemanext, Inc., Macopharma, Inc., and Forma Therapeutics.

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