Wischnewski et al. demonstrated that CD8+ T cells infiltrated breast cancer brain metastases (BC-BrM), but failed to elicit an effective antitumor immune response, in contrast to genetically identical extracranial tumors. Brain irradiation transiently elevated the lymphoid-to-myeloid cell ratio in the BrM TME, and while it did not synergize with anti-PD-1 in the BrM, this combination did exhibit synergy in extracranial tumors, suggesting an immunosuppressive role of the brain-specific TME. Transcriptional and functional analyses identified neutrophils and TREM2-expressing macrophages as key mediators of local T cell suppression within the brain.
Contributed by Shishir Pant
ABSTRACT: The brain environment is uniquely specialized to protect its neuronal tissue from excessive inflammation by tightly regulating adaptive immunity. However, in the context of brain cancer progression, this regulation can lead to a conflict between T cell activation and suppression. Here, we show that, while CD8(+) T cells can infiltrate breast cancer-brain metastases, their anti-tumor cytotoxicity is locally suppressed in the brain. Conversely, CD8(+) T cells exhibited tumoricidal activity in extracranial mammary lesions originating from the same cancer cells. Consequently, combined high-dose irradiation and anti-programmed cell death protein 1 (PD1) therapy was effective in extracranial tumors but not intracranial lesions. Transcriptional analyses and functional studies identified neutrophils and Trem2-expressing macrophages as key sources for local T cell suppression within the brain, providing rational targets for future therapeutic strategies.
Author Info: (1) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agor
Author Info: (1) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. Electronic address: vladimir.wischnewski@tron-mainz.de. (2) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. (3) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. (4) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland; Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. (5) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland. (6) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. Electronic address: johanna.joyce@unil.ch.
