Y Kudo1, C Haymaker2, J Zhang4, A Reuben4, D Y Duose2, J Fujimoto2, S Roy-Chowdhuri5, L M Solis Soto2, H Dejima2, E R Parra2, B Mino2, R Abraham2, N Ikeda6, A Vaporcyan7, D Gibbons4, J Zhang4, F F Lang8, R Luthra9, J J Lee3, C Moran5, J T Huse10, H Kadara2, I I Wistuba11. 1. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Surgery, Tokyo Medical University, Tokyo, Japan. 2. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. 3. Departments of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, USA. 4. Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. 5. Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. 6. Department of Surgery, Tokyo Medical University, Tokyo, Japan. 7. Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA. 8. Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, USA. 9. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA; Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, USA. 10. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA; Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. 11. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA; Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: iiwistuba@mdanderson.org.
Abstract
BACKGROUND: The tumor immune microenvironment (TIME) of lung cancer brain metastasis is largely unexplored. We carried out immune profiling and sequencing analysis of paired resected primary tumors and brain metastases of non-small-cell lung carcinoma (NSCLC). PATIENTS AND METHODS: TIME profiling of archival formalin-fixed and paraffin-embedded specimens of paired primary tumors and brain metastases from 39 patients with surgically resected NSCLCs was carried out using a 770 immune gene expression panel and by T-cell receptor beta repertoire (TCRβ) sequencing. Immunohistochemistry was carried out for validation. Targeted sequencing was carried out to catalog hot spot mutations in cancer genes. RESULTS: Somatic hot spot mutations were mostly shared between both tumor sites (28/39 patients; 71%). We identified 161 differentially expressed genes, indicating inhibition of dendritic cell maturation, Th1, and leukocyte extravasation signaling pathways, in brain metastases compared with primary tumors (P < 0.01). The proinflammatory cell adhesion molecule vascular cell adhesion protein 1 was significantly suppressed in brain metastases compared with primary tumors. Brain metastases exhibited lower T cell and elevated macrophage infiltration compared with primary tumors (P < 0.001). T-cell clones were expanded in 64% of brain metastases compared with their corresponding primary tumors. Furthermore, while TCR repertoires were largely shared between paired brain metastases and primary tumors, T-cell densities were sparse in the metastases. CONCLUSION: We present findings that suggest that the TIME in brain metastases from NSCLC is immunosuppressed and comprises immune phenotypes (e.g. immunosuppressive tumor-associated macrophages) that may help guide immunotherapeutic strategies for NSCLC brain metastases.
BACKGROUND: The tumor immune microenvironment (TIME) of lung cancer brain metastasis is largely unexplored. We carried out immune profiling and sequencing analysis of paired resected primary tumors and brain metastases of non-small-cell lung carcinoma (NSCLC). PATIENTS AND METHODS: TIME profiling of archival formalin-fixed and paraffin-embedded specimens of paired primary tumors and brain metastases from 39 patients with surgically resected NSCLCs was carried out using a 770 immune gene expression panel and by T-cell receptor beta repertoire (TCRβ) sequencing. Immunohistochemistry was carried out for validation. Targeted sequencing was carried out to catalog hot spot mutations in cancer genes. RESULTS: Somatic hot spot mutations were mostly shared between both tumor sites (28/39 patients; 71%). We identified 161 differentially expressed genes, indicating inhibition of dendritic cell maturation, Th1, and leukocyte extravasation signaling pathways, in brain metastases compared with primary tumors (P < 0.01). The proinflammatory cell adhesion molecule vascular cell adhesion protein 1 was significantly suppressed in brain metastases compared with primary tumors. Brain metastases exhibited lower T cell and elevated macrophage infiltration compared with primary tumors (P < 0.001). T-cell clones were expanded in 64% of brain metastases compared with their corresponding primary tumors. Furthermore, while TCR repertoires were largely shared between paired brain metastases and primary tumors, T-cell densities were sparse in the metastases. CONCLUSION: We present findings that suggest that the TIME in brain metastases from NSCLC is immunosuppressed and comprises immune phenotypes (e.g. immunosuppressive tumor-associated macrophages) that may help guide immunotherapeutic strategies for NSCLC brain metastases.
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