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

• Published in: Nature communications 2021-11, Vol.12 (1), p.6938-6938, Article 6938
• Main Authors: Lee, Alexander H., Sun, Lu, Mochizuki, Aaron Y., Reynoso, Jeremy G., Orpilla, Joey, Chow, Frances, Kienzler, Jenny C., Everson, Richard G., Nathanson, David A., Bensinger, Steven J., Liau, Linda M., Cloughesy, Timothy, Hugo, Willy, Prins, Robert M.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/51; 38; 38/91; 45; 631/67/580; 692/4028/67/1922; 692/4028/67/580; Brain - drug effects; Brain - immunology; Brain - pathology; Brain - surgery; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - immunology; Brain Neoplasms - pathology; Brain tumors; CD8 antigen; Cell activation; Chemotactic factors; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Glioblastoma; Glioblastoma - immunology; Glioblastoma - pathology; Glioblastoma - therapy; Humanities and Social Sciences; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immune system; Immunofluorescence; Immunotherapy; Interferon; Lymphocytes; Lymphocytes T; Macrophages; Metastases; Microenvironments; Monocytes; multidisciplinary; Myeloid cells; Neoadjuvant Therapy - methods; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - pathology; Neoplasm Recurrence, Local - therapy; Neurosurgical Procedures; Patients; PD-1 protein; Peripheral blood mononuclear cells; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Proteomics; RNA-Seq; Science; Science (multidisciplinary); Single-Cell Analysis; T cell receptors; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Transcriptomics; Tumor Escape - drug effects; Tumor-Associated Macrophages - drug effects; Tumor-Associated Macrophages - immunology; Tumor-infiltrating lymphocytes; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26940-2

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. Immune-checkpoint blockade has shown limited benefits in patients with glioblastoma. To understand how the composition of the tumor immune microenvironment might limit clinical responses, here the authors present a high dimensional profiling of the immune landscape in patients with glioblastoma following neoadjuvant PD-1 checkpoint blockade.