Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma
Year: 2021
Type: article
Abstract: BACKGROUND: Glioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed. METHODS: We used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations. RESULTS: ICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation. CONCLUSIONS: Our data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.
Authors: Erin F Simonds, Edbert D Lu, Oscar Badillo, Shokoufeh Karimi, Eric V Liu, Whitney Tamaki, Chiara Rancan, Kira M Downey, Jacob Stultz, Meenal Sinha, Lauren K McHenry, Nicole M Nasholm, Pavlina Chuntova, Anders Sundström, Vassilis Genoud, Shilpa A Shahani, Leo D Wang, Christine E Brown, Paul R Walker, Fredrik J Swartling, Lawrence Fong, Hideho Okada, William A Weiss, Mats Hellström
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,176
Funders: Prostate Cancer Foundation, California Institute for Regenerative Medicine, Damon Runyon Cancer Research Foundation, Samuel Waxman Cancer Research Foundation, Alex's Lemonade Stand Foundation for Childhood Cancer, Swedish Cancer Foundation, Parker Institute for Cancer Immunotherapy, Cancer Research UK, Cancerfonden, Vetenskapsrådet, National Institutes of Health, University of California, San Francisco, Uppsala Multidisciplinary Center for Advanced Computational Science, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
Awards: G1624224410, Determinants of prostate cancer sensitivity to PD-1 blockade, G2303423622, Targeting the ARHGAP25 pathway in acute myelogenous leukemia stem cells, G2651427026, Improving the efficacy of mTOR inhibition, G3321450376, UCSF DVS CyTOF Mass Cytometer, Genetic network analysis of cancer targets, G4572525476, Medical Scientist Training Program, G4756830717, Integrating mass cytometric and transcriptomic profiles of solid tumors, Inhibitors of the G protein GNAS which drives pancreatic tumorigenesis, Glioma immunotherapy targeting IDH mutation-derived epitope and immunosuppression, Immunotherapy of human bladder cancer, G6350951713, G6666824382, G6793263369, G6932267076, G712881263, G7252577870, G796431723, Integrating targeted and immunotherapy to treat genetically heterogeneous cancers, Phase I Study of Chimeric Antigen Receptor Engineered Central Memory T cells for the Treatment of Malignant Glioma, Diabetes Research Center, G893917011, Cancer Center Support Grant, Preclinical development of breakthrough immunotherapy for brain tumors, Brain Tumor SPORE Grant
OpenAlex ID: W3165096196