TY - JOUR
T1 - Single-cell transcriptomics reveals shared immunosuppressive landscapes of mouse and human neuroblastoma
AU - Costa, Ana
AU - Thirant, Cécile
AU - Kramdi, Amira
AU - Pierre-Eugène, Cécile
AU - Louis-Brennetot, Caroline
AU - Blanchard, Orphée
AU - Surdez, Didier
AU - Gruel, Nadege
AU - Lapouble, Eve
AU - Pierron, Gaëlle
AU - Sitbon, Deborah
AU - Brisse, Hervé
AU - Gauthier, Arnaud
AU - Fréneaux, Paul
AU - Bohec, Mylène
AU - Raynal, Virginie
AU - Baulande, Sylvain
AU - Leclere, Renaud
AU - Champenois, Gabriel
AU - Nicolas, Andre
AU - Meseure, Didier
AU - Bellini, Angela
AU - Marabelle, Aurelien
AU - Geoerger, Birgit
AU - Mechta-Grigoriou, Fatima
AU - Schleiermacher, Gudrun
AU - Menger, Laurie
AU - Delattre, Olivier
AU - Janoueix-Lerosey, Isabelle
N1 - Publisher Copyright:
©
PY - 2022/8/1
Y1 - 2022/8/1
N2 - Background High-risk neuroblastoma is a pediatric cancer with still a dismal prognosis, despite multimodal and intensive therapies. Tumor microenvironment represents a key component of the tumor ecosystem the complexity of which has to be accurately understood to define selective targeting opportunities, including immune-based therapies. Methods We combined various approaches including single-cell transcriptomics to dissect the tumor microenvironment of both a transgenic mouse neuroblastoma model and a cohort of 10 biopsies from neuroblastoma patients, either at diagnosis or at relapse. Features of related cells were validated by multicolor flow cytometry and functional assays. Results We show that the immune microenvironment of MYCN-driven mouse neuroblastoma is characterized by a low content of T cells, several phenotypes of macrophages and a population of cells expressing signatures of myeloid-derived suppressor cells (MDSCs) that are molecularly distinct from the various macrophage subsets. We document two cancer-associated fibroblasts (CAFs) subsets, one of which corresponding to CAF-S1, known to have immunosuppressive functions. Our data unravel a complex content in myeloid cells in patient tumors and further document a striking correspondence of the microenvironment populations between both mouse and human tumors. We show that mouse intratumor T cells exhibit increased expression of inhibitory receptors at the protein level. Consistently, T cells from patients are characterized by features of exhaustion, expressing inhibitory receptors and showing low expression of effector cytokines. We further functionally demonstrate that MDSCs isolated from mouse neuroblastoma have immunosuppressive properties, impairing the proliferation of T lymphocytes. Conclusions Our study demonstrates that neuroblastoma tumors have an immunocompromised microenvironment characterized by dysfunctional T cells and accumulation of immunosuppressive cells. Our work provides a new and precious data resource to better understand the neuroblastoma ecosystem and suggest novel therapeutic strategies, targeting both tumor cells and components of the microenvironment.
AB - Background High-risk neuroblastoma is a pediatric cancer with still a dismal prognosis, despite multimodal and intensive therapies. Tumor microenvironment represents a key component of the tumor ecosystem the complexity of which has to be accurately understood to define selective targeting opportunities, including immune-based therapies. Methods We combined various approaches including single-cell transcriptomics to dissect the tumor microenvironment of both a transgenic mouse neuroblastoma model and a cohort of 10 biopsies from neuroblastoma patients, either at diagnosis or at relapse. Features of related cells were validated by multicolor flow cytometry and functional assays. Results We show that the immune microenvironment of MYCN-driven mouse neuroblastoma is characterized by a low content of T cells, several phenotypes of macrophages and a population of cells expressing signatures of myeloid-derived suppressor cells (MDSCs) that are molecularly distinct from the various macrophage subsets. We document two cancer-associated fibroblasts (CAFs) subsets, one of which corresponding to CAF-S1, known to have immunosuppressive functions. Our data unravel a complex content in myeloid cells in patient tumors and further document a striking correspondence of the microenvironment populations between both mouse and human tumors. We show that mouse intratumor T cells exhibit increased expression of inhibitory receptors at the protein level. Consistently, T cells from patients are characterized by features of exhaustion, expressing inhibitory receptors and showing low expression of effector cytokines. We further functionally demonstrate that MDSCs isolated from mouse neuroblastoma have immunosuppressive properties, impairing the proliferation of T lymphocytes. Conclusions Our study demonstrates that neuroblastoma tumors have an immunocompromised microenvironment characterized by dysfunctional T cells and accumulation of immunosuppressive cells. Our work provides a new and precious data resource to better understand the neuroblastoma ecosystem and suggest novel therapeutic strategies, targeting both tumor cells and components of the microenvironment.
KW - Gene Expression Profiling
KW - Macrophages
KW - Myeloid-Derived Suppressor Cells
KW - Neuroblastoma
KW - Tumor Microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85136024014&partnerID=8YFLogxK
U2 - 10.1136/jitc-2022-004807
DO - 10.1136/jitc-2022-004807
M3 - Article
C2 - 36054452
AN - SCOPUS:85136024014
SN - 2051-1426
VL - 10
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 8
M1 - e004807
ER -