CD103 + regulatory T cells underlie resistance to radio-immunotherapy and impair CD8 + T cell activation in glioblastoma.

Autor: van Hooren L; Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Handgraaf SM; Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Kloosterman DJ; Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Karimi E; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.; Department of Human Genetics, McGill University, Montreal, Quebec, Canada., van Mil LWHG; Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Gassama AA; Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Solsona BG; Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., de Groot MHP; Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Brandsma D; Department of Neuro-Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands., Quail DF; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.; Department of Physiology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada., Walsh LA; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.; Department of Human Genetics, McGill University, Montreal, Quebec, Canada., Borst GR; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health and Manchester Cancer Research Centre, University of Manchester, Manchester, UK. gerben.borst@nhs.net.; Department of Radiotherapy Related Research, The Christie NHS Foundation Trust, Manchester, UK. gerben.borst@nhs.net., Akkari L; Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. l.akkari@nki.nl.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2023 May; Vol. 4 (5), pp. 665-681. Date of Electronic Publication: 2023 Apr 20.
DOI: 10.1038/s43018-023-00547-6
Abstrakt: Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy due to their low mutational burden and immunosuppressive tumor microenvironment. Here we report that fractionated radiotherapy of preclinical glioblastoma models induce a tenfold increase in T cell content. Orthogonally, spatial imaging mass cytometry shows T cell enrichment in human recurrent tumors compared with matched primary glioblastoma. In glioblastoma-bearing mice, α-PD-1 treatment applied at the peak of T cell infiltration post-radiotherapy results in a modest survival benefit compared with concurrent α-PD-1 administration. Following α-PD-1 therapy, CD103 + regulatory T cells (Tregs) with upregulated lipid metabolism accumulate in the tumor microenvironment, and restrain immune checkpoint blockade response by repressing CD8 + T cell activation. Treg targeting elicits tertiary lymphoid structure formation, enhances CD4 + and CD8 + T cell frequency and function and unleashes radio-immunotherapeutic efficacy. These results support the rational design of therapeutic regimens limiting the induction of immunosuppressive feedback pathways in the context of T cell immunotherapy in glioblastoma.
(© 2023. The Author(s).)
Databáze: MEDLINE
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