TY - JOUR
T1 - Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition
AU - Alvarez-Breckenridge, Christopher
AU - Markson, Samuel C.
AU - Stocking, Jackson H.
AU - Nayyar, Naema
AU - Lastrapes, Matt
AU - Strickland, Matthew R.
AU - Kim, Albert E.
AU - De Sauvage, Magali
AU - Dahal, Ashish
AU - Larson, Juliana M.
AU - Mora, Joana L.
AU - Navia, Andrew W.
AU - Klein, Robert H.
AU - Kuter, Benjamin M.
AU - Gill, Corey M.
AU - Bertalan, Mia
AU - Shaw, Brian
AU - Kaplan, Alexander
AU - Subramanian, Megha
AU - Jain, Aarushi
AU - Kumar, Swaminathan
AU - Danish, Husain
AU - White, Michael
AU - Shahid, Osmaan
AU - Pauken, Kristen E.
AU - Miller, Brian C.
AU - Frederick, Dennie T.
AU - Hebert, Christine
AU - Shaw, McKenzie
AU - Martinez-Lage, Maria
AU - Frosch, Matthew
AU - Wang, Nancy
AU - Gerstner, Elizabeth
AU - Nahed, Brian V.
AU - Curry, William T.
AU - Carter, Bob
AU - Cahill, Daniel P.
AU - Boland, Genevieve Marie
AU - Izar, Benjamin
AU - Davies, Michael A.
AU - Sharpe, Arlene H.
AU - Suvà, Mario L.
AU - Sullivan, Ryan J.
AU - Brastianos, Priscilla K.
AU - Carter, Scott L.
N1 - Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/8
Y1 - 2022/8
N2 - Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBMand performed single-cellRNAsequencing of theMBMTME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.
AB - Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBMand performed single-cellRNAsequencing of theMBMTME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.
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U2 - 10.1158/2326-6066.CIR-21-0870
DO - 10.1158/2326-6066.CIR-21-0870
M3 - Article
C2 - 35706413
AN - SCOPUS:85135597511
SN - 2326-6066
VL - 10
SP - 996
EP - 1012
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 8
ER -