Microenvironment analysis of mouse and human neuroblastoma reveals shared populations and unmasks various subsets of immunosuppressive cells
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PROVIDER: PRJNA746555 | ENA |
REPOSITORIES: ENA
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Project description:High-risk neuroblastoma is a pediatric cancer with dismal prognosis. In this study, we have used various approaches including single-cell RNA sequencing to dissect the tumor microenvironment of both a transgenic mouse neuroblastoma model and a cohort of biopsies from neuroblastoma patients. From the diverse cell populations identified, our data document a striking correspondence of the microenvironment populations between tumors from both species and unravel a complex content in myeloid cells and cancer-associated fibroblasts. Within the myeloid compartment we have characterized a population of cells exhibiting features of tumor-associated neutrophils and demonstrate that these cells obtained from the mouse model have immunosuppressive properties. Altogether, our study shows that neuroblastoma tumors have an immunocompromised microenvironment characterized by dysfunctional T-cells and accumulation of immunosuppressive cells. Our data provide the rationale for novel immunotherapeutic strategies in neuroblastoma, targeting both tumor cells and components of its microenvironment.
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Project description:Tumor-associated macrophages (TAM) have attracted attention as they can modulate key cancer-related activities, yet TAM represent a heterogenous group of cells that remain incompletely characterized. In growing tumors, TAM are often referred to as M2-like macrophages, which are cells that display immunosuppressive and tumorigenic functions and express the enzyme arginase 1 (Arg1). Here we combined single cell intravital imaging with scRNA seq to uncover the topography and molecular profiles of Arg1+ macrophages in mice. We further assessed how immunotherapeutic interventions impact these cells directly in vivo. We show that: i) Arg1+ macrophages are more abundant in tumors compared to other organs; ii) there exist two morphologically distinct subsets of Arg1 TAM defined by previously unknown markers (Gbp2b, Bst1, Sgk1, Pmepa1, Ms4a7); iii) anti-Programmed Cell Death-1 (aPD-1) therapy decreases the number of Arg1+ TAM while increasing Arg1– TAM; iv) accordingly, pharmacological inhibition of arginase 1 does not synergize with aPD-1 therapy. Overall, this research defines subsets of immunosuppressive myeloid cells with powerful complementary single cell analytical approaches that pave the way for a more intricate understanding of TAM behavior.
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Project description:Purpose: We aimed to link different variations of memory B cell subsets to their proliferating precursors via shared transcriptomic features. Methods : Spleens were processed according to the manuscript. Cells were collected via FACS, washed twice in PBS + 1% FCS, resuspended in 350 ul RLT Plus Buffer (Qiagen) with 1% 2-Me, and frozen at -80 ⁰C. Results: Memory cells have many DEGs in comparison to FO naïve cells. However, differences between memory cells themselves can be attributed to imprinting by their respective proliferating precursors. DP MBCs are split into two major subsets based on transcriptional state. A germinal center B cell program may be required to establish some DEGs in GC-derived memory cells.
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Project description:BackgroundHigh-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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.
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