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CD103(+) regulatory T cells underlie resistance to radio-immunotherapy and impair CD8(+) T cell activation in glioblastoma
van Hooren, L. Handgraaf, S. M. Kloosterman, D. J. Karimi, E. van Mil, L. Gassama, A. A. Solsona, B. G. de Groot, M. H. P. Brandsma, D. Quail, D. F.
van Hooren, L.
Handgraaf, S. M.
Kloosterman, D. J.
Karimi, E.
van Mil, L.
Gassama, A. A.
Solsona, B. G.
de Groot, M. H. P.
Brandsma, D.
Quail, D. F.
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Abstract
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.
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Date
2023
Publisher
Collections
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Article
Citation
van Hooren L, Handgraaf SM, Kloosterman DJ, Karimi E, van Mil L, Gassama AA, et al. CD103(+) regulatory T cells underlie resistance to radio-immunotherapy and impair CD8(+) T cell activation in glioblastoma. Nat Cancer. 2023 Apr 20. PubMed PMID: 37081259. Epub 2023/04/21. eng.