TAMI-02. DEPLETION OF INTRATUMORAL TUMOR-ASSOCIATED MACROPHAGES AND MICROGLIA (TAM/M) IMPROVES CHECKPOINT-INHIBITION THERAPY FOR BRAIN METASTASIS FROM LUNG CANCER. (12th November 2021)

• Record Type: Journal Article
• Authors: Karschnia, Philipp; Xu, Tao; Fitzinger, Esther; Saliger, Julia C; Blobner, Jens; Teske, Nico; von Muecke-Heim, Iven-Alex; Langer, Sigrid; Konhäuser, Marcel; Ishikawa-Ankerhold, Hellen; Thon, Niklas; Tonn, Jörg-Christian; von Baumgarten, Louisa
• Is Part Of: Neuro-oncology. Volume 23: Supplement 6(2021)
• Page Start: vi198
• Page End: vi198
• Publication Date: 2021-11-12
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab196.786
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: Brain metastases dramatically limit prognosis of lung cancer patients. Unlike systemic disease, brain metastases from lung cancer poorly respond to checkpoint-inhibition therapy. Targeting the immunosuppressive tumor-associated macrophages and microglia (TAM/M) and their receptor CSF1R may increase efficacy of checkpoint-inhibitors. METHODS: Cranial windows were prepared in fully immunocompetent, transgenic CX3CR1 GFP/wt -mice with green-fluorescent TAM/M. Intracranial injection of red-fluorescent Lewis Lung Carcinoma-cells was performed, and mice received one of the following three treatments: PD1-inhibition only (n = 8); PD1-inhibition combined with an anti-CSF1R-antibody (exhibiting limited blood-brain-barrier permeability under physiologic conditions, n = 8); or PD1-inhibition combined with a small molecular CSF1R-inhibitor (exhibiting high blood-brain-barrier permeability, n = 7). Tumor growth and TAM/M were followed by repetitive two-photon laser-scanning-microscopy over weeks. RESULTS: Following intracranial injection, metastases were detected in all three treatment groups within eight days. In mice receiving PD1-inhibition only, metastases showed exponential growth which was paralleled by intra- and peritumoral accumulation of TAM/M. Treatment with an anti-CSF1R-antibody resulted in significantly lower numbers of intratumoral TAM/M given increased tumoral blood-brain-barrier permeability, but did not substantially affect peritumoral TAM/M or TAM/M localized in the healthy contralateral hemisphere. In contrast, treatment with a small molecular CSF1R-inhibitor not only reduced the number of intratumoral TAM/M, but also of peritumoral and contralateral TAM/M. Compared to PD1-inhibition only, the addition of either an anti-CSF1R-antibody or a small molecular CSF1R-inhibitor resulted in decreased tumor growth (tumor size on day 12: 8.3 mm 2 (PD1-inhibition only) versus 0.9 mm 2 (PD1-inhibition + anti-CSF1R-antibody) versus 2.5 mm 2 (PD1-inhibition + small molecular CSF1R-inhibitor)) ( p = 0.01). The beneficial effects of the small molecular CSF1R-inhibitor in reducing tumor growth were similar to those of the anti-CSF1R-antibody. CONCLUSION: Targeting intratumoral TAM/M using CSF1-inhibition may increase the efficacy of checkpoint-inhibition therapy for cerebral lung cancer metastases. This approach warrants further evaluation in preclinical and clinical studies.