Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target

Nourhan Abdelfattah; Parveen Kumar; Caiyi Wang; Jia Shiun Leu; William F. Flynn; Ruli Gao; David S. Baskin; Kumar Pichumani; Omkar B. Ijare; Stephanie L. Wood; Suzanne Z. Powell; David L. Haviland; Brittany C. Parker Kerrigan; Frederick F. Lang; Sujit S. Prabhu; Kristin M. Huntoon; Wen Jiang; Betty Y.S. Kim; Joshy George; Kyuson Yun

doi:10.1038/s41467-022-28372-y

Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target

Nourhan Abdelfattah, Parveen Kumar, Caiyi Wang, Jia Shiun Leu, William F. Flynn, Ruli Gao, David S. Baskin, Kumar Pichumani, Omkar B. Ijare, Stephanie L. Wood, Suzanne Z. Powell, David L. Haviland, Brittany C. Parker Kerrigan, Frederick F. Lang, Sujit S. Prabhu, Kristin M. Huntoon, Wen Jiang, Betty Y.S. Kim, Joshy George, Kyuson Yun

Research output: Contribution to journal › Article › peer-review

111 Scopus citations

Abstract

A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer.

Original language	English (US)
Article number	767
Pages (from-to)	767
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-28372-y https://doi.org/10.1038/s41467-022-28372-y
State	Published - Feb 9 2022

Keywords

Animals
Brain Neoplasms/immunology
Female
Glioma/immunology
Humans
Immunotherapy
Male
Mice
Mice, Inbred C57BL
Myeloid Cells
Prognosis
S100 Calcium-Binding Protein A4/genetics
Single-Cell Analysis/methods
Tumor Microenvironment/immunology

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Abdelfattah, N., Kumar, P., Wang, C., Leu, J. S., Flynn, W. F., Gao, R., Baskin, D. S., Pichumani, K., Ijare, O. B., Wood, S. L., Powell, S. Z., Haviland, D. L., Parker Kerrigan, B. C., Lang, F. F., Prabhu, S. S., Huntoon, K. M., Jiang, W., Kim, B. Y. S., George, J., & Yun, K. (2022). Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target. Nature Communications, 13(1), 767. Article 767. https://doi.org/10.1038/s41467-022-28372-y, https://doi.org/10.1038/s41467-022-28372-y

Abdelfattah, N, Kumar, P, Wang, C, Leu, JS, Flynn, WF, Gao, R, Baskin, DS , Pichumani, K , Ijare, OB, Wood, SL, Powell, SZ, Haviland, DL, Parker Kerrigan, BC, Lang, FF, Prabhu, SS, Huntoon, KM, Jiang, W, Kim, BYS, George, J & Yun, K 2022, 'Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target', Nature Communications, vol. 13, no. 1, 767, pp. 767. https://doi.org/10.1038/s41467-022-28372-y, https://doi.org/10.1038/s41467-022-28372-y

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abstract = "A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer.",

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author = "Nourhan Abdelfattah and Parveen Kumar and Caiyi Wang and Leu, {Jia Shiun} and Flynn, {William F.} and Ruli Gao and Baskin, {David S.} and Kumar Pichumani and Ijare, {Omkar B.} and Wood, {Stephanie L.} and Powell, {Suzanne Z.} and Haviland, {David L.} and {Parker Kerrigan}, {Brittany C.} and Lang, {Frederick F.} and Prabhu, {Sujit S.} and Huntoon, {Kristin M.} and Wen Jiang and Kim, {Betty Y.S.} and Joshy George and Kyuson Yun",

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AU - Flynn, William F.

AU - Gao, Ruli

AU - Baskin, David S.

AU - Pichumani, Kumar

AU - Ijare, Omkar B.

AU - Wood, Stephanie L.

AU - Powell, Suzanne Z.

AU - Haviland, David L.

AU - Parker Kerrigan, Brittany C.

AU - Lang, Frederick F.

AU - Prabhu, Sujit S.

AU - Huntoon, Kristin M.

AU - Jiang, Wen

AU - Kim, Betty Y.S.

AU - George, Joshy

AU - Yun, Kyuson

PY - 2022/2/9

Y1 - 2022/2/9

N2 - A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer.

AB - A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer.

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KW - Myeloid Cells

KW - Prognosis

KW - S100 Calcium-Binding Protein A4/genetics

KW - Single-Cell Analysis/methods

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Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target

Abstract

Keywords

ASJC Scopus subject areas

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