Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment. Müller, S., Kohanbash, G., Liu, S J., Alvarado, B., Carrera, D., Bhaduri, A., Watchmaker, P. B, Yagnik, G., Di Lullo, E., Malatesta, M., Amankulor, N. M, Kriegstein, A. R, Lim, D. A, Aghi, M., Okada, H., & Diaz, A. Genome Biol, 18(1):234, December, 2017. abstract bibtex BACKGROUND: Tumor-associated macrophages (TAMs) are abundant in gliomas and immunosuppressive TAMs are a barrier to emerging immunotherapies. It is unknown to what extent macrophages derived from peripheral blood adopt the phenotype of brain-resident microglia in pre-treatment gliomas. The relative proportions of blood-derived macrophages and microglia have been poorly quantified in clinical samples due to a paucity of markers that distinguish these cell types in malignant tissue. RESULTS: We perform single-cell RNA-sequencing of human gliomas and identify phenotypic differences in TAMs of distinct lineages. We isolate TAMs from patient biopsies and compare them with macrophages from non-malignant human tissue, glioma atlases, and murine glioma models. We present a novel signature that distinguishes TAMs by ontogeny in human gliomas. Blood-derived TAMs upregulate immunosuppressive cytokines and show an altered metabolism compared to microglial TAMs. They are also enriched in perivascular and necrotic regions. The gene signature of blood-derived TAMs, but not microglial TAMs, correlates with significantly inferior survival in low-grade glioma. Surprisingly, TAMs frequently co-express canonical pro-inflammatory (M1) and alternatively activated (M2) genes in individual cells. CONCLUSIONS: We conclude that blood-derived TAMs significantly infiltrate pre-treatment gliomas, to a degree that varies by glioma subtype and tumor compartment. Blood-derived TAMs do not universally conform to the phenotype of microglia, but preferentially express immunosuppressive cytokines and show an altered metabolism. Our results argue against status quo therapeutic strategies that target TAMs indiscriminately and in favor of strategies that specifically target immunosuppressive blood-derived TAMs.
@ARTICLE{Muller2017-zp,
title = "Single-cell profiling of human gliomas reveals macrophage
ontogeny as a basis for regional differences in macrophage
activation in the tumor microenvironment",
author = "M{\"u}ller, S{\"o}ren and Kohanbash, Gary and Liu, S John and
Alvarado, Beatriz and Carrera, Diego and Bhaduri, Aparna and
Watchmaker, Payal B and Yagnik, Garima and Di Lullo, Elizabeth
and Malatesta, Martina and Amankulor, Nduka M and Kriegstein,
Arnold R and Lim, Daniel A and Aghi, Manish and Okada, Hideho and
Diaz, Aaron",
abstract = "BACKGROUND: Tumor-associated macrophages (TAMs) are abundant in
gliomas and immunosuppressive TAMs are a barrier to emerging
immunotherapies. It is unknown to what extent macrophages derived
from peripheral blood adopt the phenotype of brain-resident
microglia in pre-treatment gliomas. The relative proportions of
blood-derived macrophages and microglia have been poorly
quantified in clinical samples due to a paucity of markers that
distinguish these cell types in malignant tissue. RESULTS: We
perform single-cell RNA-sequencing of human gliomas and identify
phenotypic differences in TAMs of distinct lineages. We isolate
TAMs from patient biopsies and compare them with macrophages from
non-malignant human tissue, glioma atlases, and murine glioma
models. We present a novel signature that distinguishes TAMs by
ontogeny in human gliomas. Blood-derived TAMs upregulate
immunosuppressive cytokines and show an altered metabolism
compared to microglial TAMs. They are also enriched in
perivascular and necrotic regions. The gene signature of
blood-derived TAMs, but not microglial TAMs, correlates with
significantly inferior survival in low-grade glioma.
Surprisingly, TAMs frequently co-express canonical
pro-inflammatory (M1) and alternatively activated (M2) genes in
individual cells. CONCLUSIONS: We conclude that blood-derived
TAMs significantly infiltrate pre-treatment gliomas, to a degree
that varies by glioma subtype and tumor compartment.
Blood-derived TAMs do not universally conform to the phenotype of
microglia, but preferentially express immunosuppressive cytokines
and show an altered metabolism. Our results argue against status
quo therapeutic strategies that target TAMs indiscriminately and
in favor of strategies that specifically target immunosuppressive
blood-derived TAMs.",
journal = "Genome Biol",
volume = 18,
number = 1,
pages = "234",
month = dec,
year = 2017,
keywords = "Glioma; Immunotherapy; Macrophage; Single-cell sequencing",
language = "en"
}
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A","Aghi, M.","Okada, H.","Diaz, A."],"bibdata":{"bibtype":"article","type":"article","title":"Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment","author":[{"propositions":[],"lastnames":["Müller"],"firstnames":["Sören"],"suffixes":[]},{"propositions":[],"lastnames":["Kohanbash"],"firstnames":["Gary"],"suffixes":[]},{"propositions":[],"lastnames":["Liu"],"firstnames":["S","John"],"suffixes":[]},{"propositions":[],"lastnames":["Alvarado"],"firstnames":["Beatriz"],"suffixes":[]},{"propositions":[],"lastnames":["Carrera"],"firstnames":["Diego"],"suffixes":[]},{"propositions":[],"lastnames":["Bhaduri"],"firstnames":["Aparna"],"suffixes":[]},{"propositions":[],"lastnames":["Watchmaker"],"firstnames":["Payal","B"],"suffixes":[]},{"propositions":[],"lastnames":["Yagnik"],"firstnames":["Garima"],"suffixes":[]},{"propositions":[],"lastnames":["Di","Lullo"],"firstnames":["Elizabeth"],"suffixes":[]},{"propositions":[],"lastnames":["Malatesta"],"firstnames":["Martina"],"suffixes":[]},{"propositions":[],"lastnames":["Amankulor"],"firstnames":["Nduka","M"],"suffixes":[]},{"propositions":[],"lastnames":["Kriegstein"],"firstnames":["Arnold","R"],"suffixes":[]},{"propositions":[],"lastnames":["Lim"],"firstnames":["Daniel","A"],"suffixes":[]},{"propositions":[],"lastnames":["Aghi"],"firstnames":["Manish"],"suffixes":[]},{"propositions":[],"lastnames":["Okada"],"firstnames":["Hideho"],"suffixes":[]},{"propositions":[],"lastnames":["Diaz"],"firstnames":["Aaron"],"suffixes":[]}],"abstract":"BACKGROUND: Tumor-associated macrophages (TAMs) are abundant in gliomas and immunosuppressive TAMs are a barrier to emerging immunotherapies. It is unknown to what extent macrophages derived from peripheral blood adopt the phenotype of brain-resident microglia in pre-treatment gliomas. The relative proportions of blood-derived macrophages and microglia have been poorly quantified in clinical samples due to a paucity of markers that distinguish these cell types in malignant tissue. RESULTS: We perform single-cell RNA-sequencing of human gliomas and identify phenotypic differences in TAMs of distinct lineages. We isolate TAMs from patient biopsies and compare them with macrophages from non-malignant human tissue, glioma atlases, and murine glioma models. We present a novel signature that distinguishes TAMs by ontogeny in human gliomas. Blood-derived TAMs upregulate immunosuppressive cytokines and show an altered metabolism compared to microglial TAMs. They are also enriched in perivascular and necrotic regions. The gene signature of blood-derived TAMs, but not microglial TAMs, correlates with significantly inferior survival in low-grade glioma. Surprisingly, TAMs frequently co-express canonical pro-inflammatory (M1) and alternatively activated (M2) genes in individual cells. CONCLUSIONS: We conclude that blood-derived TAMs significantly infiltrate pre-treatment gliomas, to a degree that varies by glioma subtype and tumor compartment. Blood-derived TAMs do not universally conform to the phenotype of microglia, but preferentially express immunosuppressive cytokines and show an altered metabolism. Our results argue against status quo therapeutic strategies that target TAMs indiscriminately and in favor of strategies that specifically target immunosuppressive blood-derived TAMs.","journal":"Genome Biol","volume":"18","number":"1","pages":"234","month":"December","year":"2017","keywords":"Glioma; Immunotherapy; Macrophage; Single-cell sequencing","language":"en","bibtex":"@ARTICLE{Muller2017-zp,\n title = \"Single-cell profiling of human gliomas reveals macrophage\n ontogeny as a basis for regional differences in macrophage\n activation in the tumor microenvironment\",\n author = \"M{\\\"u}ller, S{\\\"o}ren and Kohanbash, Gary and Liu, S John and\n Alvarado, Beatriz and Carrera, Diego and Bhaduri, Aparna and\n Watchmaker, Payal B and Yagnik, Garima and Di Lullo, Elizabeth\n and Malatesta, Martina and Amankulor, Nduka M and Kriegstein,\n Arnold R and Lim, Daniel A and Aghi, Manish and Okada, Hideho and\n Diaz, Aaron\",\n abstract = \"BACKGROUND: Tumor-associated macrophages (TAMs) are abundant in\n gliomas and immunosuppressive TAMs are a barrier to emerging\n immunotherapies. It is unknown to what extent macrophages derived\n from peripheral blood adopt the phenotype of brain-resident\n microglia in pre-treatment gliomas. The relative proportions of\n blood-derived macrophages and microglia have been poorly\n quantified in clinical samples due to a paucity of markers that\n distinguish these cell types in malignant tissue. RESULTS: We\n perform single-cell RNA-sequencing of human gliomas and identify\n phenotypic differences in TAMs of distinct lineages. We isolate\n TAMs from patient biopsies and compare them with macrophages from\n non-malignant human tissue, glioma atlases, and murine glioma\n models. We present a novel signature that distinguishes TAMs by\n ontogeny in human gliomas. Blood-derived TAMs upregulate\n immunosuppressive cytokines and show an altered metabolism\n compared to microglial TAMs. They are also enriched in\n perivascular and necrotic regions. The gene signature of\n blood-derived TAMs, but not microglial TAMs, correlates with\n significantly inferior survival in low-grade glioma.\n Surprisingly, TAMs frequently co-express canonical\n pro-inflammatory (M1) and alternatively activated (M2) genes in\n individual cells. CONCLUSIONS: We conclude that blood-derived\n TAMs significantly infiltrate pre-treatment gliomas, to a degree\n that varies by glioma subtype and tumor compartment.\n Blood-derived TAMs do not universally conform to the phenotype of\n microglia, but preferentially express immunosuppressive cytokines\n and show an altered metabolism. Our results argue against status\n quo therapeutic strategies that target TAMs indiscriminately and\n in favor of strategies that specifically target immunosuppressive\n blood-derived TAMs.\",\n journal = \"Genome Biol\",\n volume = 18,\n number = 1,\n pages = \"234\",\n month = dec,\n year = 2017,\n keywords = \"Glioma; Immunotherapy; Macrophage; Single-cell sequencing\",\n language = \"en\"\n}\n\n","author_short":["Müller, S.","Kohanbash, G.","Liu, S J.","Alvarado, B.","Carrera, D.","Bhaduri, A.","Watchmaker, P. B","Yagnik, G.","Di Lullo, E.","Malatesta, M.","Amankulor, N. M","Kriegstein, A. R","Lim, D. 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