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

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.

Spatial proteomic analysis of a lung cancer model reveals regulatory T cells attenuate KRAS-G12C inhibitor-induced immune responses

“…This suggests that DC, T cell and Treg rich communities are a recurring feature in lung cancer and may predict response in a broader context. Several studies in lung cancer so far have indicated frequencies of intra-tumoral or circulating Tregs to be associated with poor outcome ( 51–53 ) or therapy resistance( 54, 55 ), but few have looked into the cellular communities in more detail.…”

Tertiary lymphoid structures in cancer: maturation and induction

“…Glioma poses a significant challenge due to its immunosuppressive microenvironment. Studies have shown that combining radiotherapy with targeted Tregs interventions induces massive T cell-infiltration and the development of meningeal TLS, effectively activating the TME in preclinical glioma models ( 16 ). Low-dose radiotherapy has been found to trigger the development of immature TLS in a mouse model of lung cancer.…”

“…For example, vaccination with the human papillomavirus (HPV) oncoprotein vaccine and the pancreatic cancer vaccine induce the formation of TLS ( 14 , 15 ). Radiotherapy combined with targeted Tregs therapy improve the immunosuppressive microenvironment of glioma and induce the formation of meningeal TLS ( 16 ). This review provides a comprehensive overview of TLS formation, detection, maturity, and induction through various cancer treatments, highlighting the clinical significance of TLS and laying the groundwork for future anti-cancer therapies that target TLS formation.…”

The diversity and dynamics of tumor-associated macrophages in recurrent glioblastoma

“…EGFRvIII is an immunogenic mutation widely detected and constitutively activated in primary GBM, indicating that immunologic escape occured after a period of progression-free survival in rGBM ( 26 ). Recently, it was reported that CD103 + Tregs with upregulated lipid metabolism accumulated in response to ICB therapy and concurrent radiotherapy, which hindered the cytotoxic activity of CTLs in GBM ( 27 ). Additionally, rGBM exhibited an increase in the infiltration of CD68 + macrophages following anti-angiogenic therapy, suggestive of the potential role of TAMs in controlling therapeutic resistance and tumor relapse ( 15 ).…”