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.