Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma

Abstract

Primary brain tumors, such as glioblastoma (GBM), are remarkably resistant to immunotherapy, even though pre-clinical models suggest effectiveness. To understand this better in patients, here we take advantage of our recent neoadjuvant treatment paradigm to map the infiltrating immune cell landscape of GBM and how this is altered following PD-1 checkpoint blockade using high dimensional proteomics, single cell transcriptomics, and quantitative multiplex immunofluorescence. Neoadjuvant PD-1 blockade increases T cell infiltration and the proportion of a progenitor exhausted population of T cells found within the tumor. We identify an early activated and clonally expanded CD8+ T cell cluster whose TCR overlaps with a CD8+ PBMC population. Distinct changes are also observed in conventional type 1 dendritic cells that may facilitate T cell recruitment. Macrophages and monocytes still constitute the majority of infiltrating immune cells, even after anti-PD-1 therapy. Interferon-mediated changes in the myeloid population are consistently observed following PD-1 blockade; these also mediate an increase in chemotactic factors that recruit T cells. However, sustained high expression of T-cell-suppressive checkpoints in these myeloid cells continue to prevent the optimal activation of the tumor infiltrating T cells. Therefore, future immunotherapeutic strategies may need to incorporate the targeting of these cells for clinical benefit.

The Role of m6A Regulator-Mediated Methylation Modification and Tumor Microenvironment Infiltration in Glioblastoma Multiforme

“…To analyze the association of m6AScore with immunotherapy, we collected three cohorts of patients with metastatic melanoma treated with anti-PD-1 therapy ( Hugo et al, 2016 ), patients with metastatic uroepithelial cancer treated with anti-PD-L1 therapy ( Mariathasan et al, 2018 ), patients with GBM treated with anti-PD-1 therapy ( Lee et al, 2021 ) ( Cloughesy et al, 2019 ). To investigate the differences in the extent to which m6A modifications affect immunity and stemness, immune markers and typical BP were introduced to compare the potential mechanisms of the different clusters.…”

Glioma targeted therapy: insight into future of molecular approaches

“…Tumor-associated macrophages (TAMs), a significant component of tumor microenvironment, in glioma, are commonly defined as macrophages of peripheral origin and microglia, to regulate immune response and promote tumor progression [ 299 , 300 ]. A recent study demonstrated that despite of inducing T cell and DC activation, neoadjuvant PD-1 blockade failed to overcome the immunosuppressive TAMs in rGBM, indicating the important role of TAM in resistance to treatment [ 301 ].…”

Cancer cell membrane-coated nanoparticles for bimodal imaging-guided photothermal therapy and docetaxel-enhanced immunotherapy against cancer

“…Some studies have demonstrated that DTX can effectively reverse the immunosuppressive TME by polarizing protumoral M2-phenotype TAMs to tumoricidal M1-phenotype TAMs [ 24 ]. Immunotherapy has received increasing attention due to its ability to activate host defenses to identify, attack, and eradicate cancer cells [ 70 , 71 ]. However, low immune response rate and individual differences undermine its antitumor efficacy.…”