Selective targeting of IL2Rβγ combined with radiotherapy triggers CD8- and NK-mediated immunity, abrogating metastasis in HNSCC.

Humans Squamous Cell Carcinoma of Head and Neck / radiotherapy Interleukin-2 / pharmacology Interleukin-2 Receptor alpha Subunit T-Lymphocytes, Cytotoxic Head and Neck Neoplasms / radiotherapy
IL-2 Tregs cancer head and neck cancer immunocytokine immunotherapy metastasis natural killer cells radiation therapy tumor immunology

Journal

Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894

Informations de publication

Date de publication:
15 08 2023
Historique:
received: 06 07 2022
revised: 21 04 2023
accepted: 18 07 2023
medline: 18 8 2023
pubmed: 17 8 2023
entrez: 16 8 2023
Statut: ppublish

Résumé

The implementation of cancer immunotherapies has seen limited clinical success in head and neck squamous cell carcinoma (HNSCC). Interleukin-2 (IL-2), which modulates the survival and functionality of lymphocytes, is an attractive target for new immunotherapies but one that is limited by presence of regulatory T cells (Tregs) expressing the high-affinity IL-2Rα. The bispecific immunocytokine PD1-IL2v preferentially delivers IL-2 signaling through IL-2Rβγ on PD-1-expressing cells. Selectively targeting the intermediate-affinity IL-2Rβγ can be leveraged to induce anti-tumor immune responses in effector T cells and natural killer (NK) cells while limiting the negative regulation of IL-2Rα activation on Tregs. Using radiation therapy (RT) in combination with PD1-IL2v improves local tumor control and survival, and controls metastatic spread in orthotopic HNSCC tumor models. PD1-IL2v drives systemic activation and expansion of circulating and tumor-infiltrating cytotoxic T cells and NK cells while limiting Treg-mediated immunosuppression. These data show that PD1-L2v induces durable systemic tumor control in HNSCC.

Identifiants

DOI: 10.1016/j.xcrm.2023.101150 PMID: 37586327 PMC: PMC10439274
pubmed: 37586327
pii: S2666-3791(23)00303-8
doi: 10.1016/j.xcrm.2023.101150
pmc: PMC10439274
pii:
doi:

Substances chimiques

Interleukin-2 0
Interleukin-2 Receptor alpha Subunit 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

101150

Subventions

Organisme : NCI NIH HHS
ID : P50 CA261605
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA261605
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028282
Pays : United States

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests M.A., L.C.D., P.U., and C.K. are employed by Roche Innovation Center Zurich and declare ownership of stock and patents with Roche. S.D.K. receives funding from NIDCR/NCI in addition to clinical trial funding from AstraZeneca, Genentech, and Ionis outside the submitted work. S.D.K. reports no personal payment in consulting, advisory boards, clinical trials, or any other relevant financial disclosures. 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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Auteurs

Jacob Gadwa (J)

Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Immunology & Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Maria Amann (M)

Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), 8952 Schlieren, Switzerland.

Thomas E Bickett (TE)

Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Michael W Knitz (MW)

Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Laurel B Darragh (LB)

Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Immunology & Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Miles Piper (M)

Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Benjamin Van Court (B)

Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Sanjana Bukkapatnam (S)

Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Tiffany T Pham (TT)

Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Xiao-Jing Wang (XJ)

Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Anthony J Saviola (AJ)

Department of Biochemistry and Molecular Genetics, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Laura Codarri Deak (LC)

Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), 8952 Schlieren, Switzerland.

Pablo Umaña (P)

Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), 8952 Schlieren, Switzerland.

Christian Klein (C)

Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), 8952 Schlieren, Switzerland.

Angelo D'Alessandro (A)

Department of Biochemistry and Molecular Genetics, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Sana D Karam (SD)

Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Immunology & Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: sana.karam@cuanschutz.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Selective targeting of IL2Rβγ combined with...
questionsmedicales.fr › Tumeurs › Tumeurs par siège › Tumeurs de la tête et du cou › Carcinome épidermoïde de la tête et du cou › Selective targeting of IL2Rβγ combined with...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Lymphokines › Interleukine-2 › Selective targeting of IL2Rβγ combined with...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Récepteurs aux cytokines › Récepteurs aux interleukines › Récepteurs à l'interleukine-2 › Sous-unité alpha du récepteur à l'interleukine-2 › Selective targeting of IL2Rβγ combined with...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Sous-populations de lymphocytes T › Lymphocytes T cytotoxiques › Selective targeting of IL2Rβγ combined with...
questionsmedicales.fr › Tumeurs › Tumeurs par siège › Tumeurs de la tête et du cou › Selective targeting of IL2Rβγ combined with...