Wenya Linda Bi1, Saksham Gupta1, Yu Mei2, Sally Al Abdulmohsen1, Alexandra Giantini Larsen1, Prashin Unadkat1, Shakti Ramkissoon3,4, Malak Abedalthagafi5, Ian F Dunn6. 1. Center for Skull Base and Pituitary Surgery, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School. 2. Department of Pathology, Boston Children's Hospital, Boston, Massachusetts. 3. Wake Forest Comprehensive Cancer Center and Department of Pathology, Wake Forest School of Medicine, Winston-Salem. 4. Foundation Medicine, Inc., Morrisville, North Carolina, USA. 5. Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudia Arabia. 6. Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Abstract
BACKGROUND: Vestibular schwannomas exhibit a uniquely variable natural history of growth, stability, or even spontaneous regression. We hypothesized that a transitory population of immune cells, or immunomodulation of tumors cells, may influence the growth pattern of schwannomas. We therefore sought to characterize the impact of the immune microenvironment on schwannoma behavior. METHODS: Forty-eight vestibular schwannomas with preoperative magnetic resonance imaging and 11 with serial imaging were evaluated for presence of immune infiltrates (including the pan-leukocyte marker Cluster of Differentiation (CD)45, CD4 and CD8 T-cell, and CD68 and CD163 macrophages) as well as expression of immunomodulatory regulators (Programmed Death Ligand 1 (PD-L1), Programmed Death Ligand 2 (PD-L2), LAG-3, TIM-3, V-domain Ig Suppressor of T cell Activation). Maximal diameter, volume, and recurrence were annotated. RESULTS: Vestibular schwannomas were characterized by diverse signatures of tumor infiltrating leukocytes and immunomodulatory markers. The median tumor volume was 4.7 cm (Interquartile Range (IQR) 1.0-13.0) and maximum diameter was 2.3 cm (IQR 1.5-3.2). Among tumors with serial imaging, the median volumetric growth was 0.04 cm/mo (IQR 0.01-0.18). Tumor volume and maximum diameter demonstrated strong concordance (R = 0.90; p < 0.001). Vestibular schwannoma volume was positively associated with CD4, CD68, and CD163, but not CD8, immune infiltration (all p < 0.05). Tumor growth was positively associated with CD163 and PD-L1 (both p < 0.05). Further, CD163 modified this effect: the relationship between PD-L1 and growth strengthened with increasing CD163 infiltration (R = 0.81, p = 0.007). No other immune cell types modified this relationship. These associations were inconsistently observed for maximum diameter and linear growth. CONCLUSION: Vestibular schwannomas demonstrate variable expression of immune regulatory markers as well as immune infiltrates. Tumor size is associated with immune infiltrates and tumor growth is associated with PD-L1, especially in the presence of M2-subtype macrophages. Volumetric measures may associate with the biological signature more accurately than linear parameters. Future exploration of the role of immune modulation in select schwannomas will further enhance our understanding of the biology of these tumors and suggest potential therapeutic avenues for control of tumor growth.
BACKGROUND:Vestibular schwannomas exhibit a uniquely variable natural history of growth, stability, or even spontaneous regression. We hypothesized that a transitory population of immune cells, or immunomodulation of tumors cells, may influence the growth pattern of schwannomas. We therefore sought to characterize the impact of the immune microenvironment on schwannoma behavior. METHODS: Forty-eight vestibular schwannomas with preoperative magnetic resonance imaging and 11 with serial imaging were evaluated for presence of immune infiltrates (including the pan-leukocyte marker Cluster of Differentiation (CD)45, CD4 and CD8 T-cell, and CD68 and CD163 macrophages) as well as expression of immunomodulatory regulators (Programmed Death Ligand 1 (PD-L1), Programmed Death Ligand 2 (PD-L2), LAG-3, TIM-3, V-domain Ig Suppressor of T cell Activation). Maximal diameter, volume, and recurrence were annotated. RESULTS:Vestibular schwannomas were characterized by diverse signatures of tumor infiltrating leukocytes and immunomodulatory markers. The median tumor volume was 4.7 cm (Interquartile Range (IQR) 1.0-13.0) and maximum diameter was 2.3 cm (IQR 1.5-3.2). Among tumors with serial imaging, the median volumetric growth was 0.04 cm/mo (IQR 0.01-0.18). Tumor volume and maximum diameter demonstrated strong concordance (R = 0.90; p < 0.001). Vestibular schwannoma volume was positively associated with CD4, CD68, and CD163, but not CD8, immune infiltration (all p < 0.05). Tumor growth was positively associated with CD163 and PD-L1 (both p < 0.05). Further, CD163 modified this effect: the relationship between PD-L1 and growth strengthened with increasing CD163 infiltration (R = 0.81, p = 0.007). No other immune cell types modified this relationship. These associations were inconsistently observed for maximum diameter and linear growth. CONCLUSION:Vestibular schwannomas demonstrate variable expression of immune regulatory markers as well as immune infiltrates. Tumor size is associated with immune infiltrates and tumor growth is associated with PD-L1, especially in the presence of M2-subtype macrophages. Volumetric measures may associate with the biological signature more accurately than linear parameters. Future exploration of the role of immune modulation in select schwannomas will further enhance our understanding of the biology of these tumors and suggest potential therapeutic avenues for control of tumor growth.
Authors: Eric Nisenbaum; Carly Misztal; Mikhaylo Szczupak; Torin Thielhelm; Stefanie Peña; Christine Mei; Stefania Goncalves; Olena Bracho; Ruixuan Ma; Michael E Ivan; Jacques Morcos; Fred Telischi; Xue-Zhong Liu; Cristina Fernandez-Valle; Christine T Dinh Journal: OTO Open Date: 2021-11-23