Investigating the sequencing of radiotherapy (RT) and ICB in preclinical glioblastoma models, Van Hooren and Handgraaf et al. found that RT increased T cells, and that administration of anti-PD-1 at the peak of RT-induced T cell infiltration enhanced survival over concurrent RT + anti-PD-1. However, anti-PD-1 induced an accumulation of CD103+ Tregs with upregulated lipid metabolism, which repressed CD8+ T cell activation and restrained antitumor responses. Adding anti-CD25 to deplete most Tregs increased the formation of TLSs and the priming and frequency of CD4+ and CD8+ T cells, improving responses to RT + anti-PD-1.
Contributed by Lauren Hitchings
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.
Author Info: (1) Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Division of Tumor Biology and Immunology, Oncode I
Author Info: (1) Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (3) Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (4) Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. Department of Human Genetics, McGill University, Montreal, Quebec, Canada. (5) Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (6) Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (7) Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (8) Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (9) Department of Neuro-Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands. (10) Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. Department of Physiology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. (11) Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. Department of Human Genetics, McGill University, Montreal, Quebec, Canada. (12) 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. (13) Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. l.akkari@nki.nl.
