Myeloid-cell derived oxidized lipids and regulation of the tumor microenvironment

2021 ◽  
pp. canres.3054.2021
Author(s):  
Kristin C Hicks ◽  
Yulia Y Tyurina ◽  
Valerian E Kagan ◽  
Dmitry I Gabrilovich
Keyword(s):  
Tumor Microenvironment ◽  
Myeloid Cell ◽  
Oxidized Lipids

scholarly journals Single-cell RNA Sequencing Reveals Immunosuppressive Myeloid Cell Diversity and Restricted Cytotoxic Effector Cell Trafficking and Activation During Malignant Progression in Glioma

2021 ◽  
Author(s):  
Sakthi Rajendran ◽  
Clayton Peterson ◽  
Alessandro Canella ◽  
Yang Hu ◽  
Amy Gross ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Malignant Progression ◽  
Low Grade ◽  
Cell Trafficking ◽  
High Grade ◽  
Single Cell Rna Sequencing

Low grade gliomas (LGG) account for about two-thirds of all glioma diagnoses in adolescents and young adults (AYA) and malignant progression of these patients leads to dismal outcomes. Recent studies have shown the importance of the dynamic tumor microenvironment in high-grade gliomas (HGG), yet its role is still poorly understood in low-grade glioma malignant progression. Here, we investigated the heterogeneity of the immune microenvironment using a platelet-derived growth factor (PDGF)-driven RCAS (replication-competent ASLV long terminal repeat with a splice acceptor) glioma model that recapitulates the malignant progression of low to high-grade glioma in humans and also provides a model system to characterize immune cell trafficking and evolution. To illuminate changes in the immune cell landscape during tumor progression, we performed single-cell RNA sequencing on immune cells isolated from animals bearing no tumor (NT), LGG and HGG, with a particular focus on the myeloid cell compartment, which is known to mediate glioma immunosuppression. LGGs demonstrated significantly increased infiltrating T cells, CD4 T cells, CD8 T cells, B cells, and natural killer cells in the tumor microenvironment, whereas HGGs significantly abrogated this infiltration. Our study identified two distinct macrophage clusters in the tumor microenvironment; one cluster appeared to be bone marrow-derived while another was defined by overexpression of Trem2, a marker of tumor associated macrophages. Our data demonstrates that these two distinct macrophage clusters show an immune-activated phenotype (Stat1, Tnf, Cxcl9 and Cxcl10) in LGG which evolves to an immunosuppressive state (Lgals3, Apoc1 and Id2) in HGG that restricts T cell recruitment and activation. We identified CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Interestingly, these results were mirrored by our analysis of the TCGA dataset, which demonstrated a statistically significant association between CD74 overexpression and decreased overall survival in AYA patients with grade II gliomas. Targeting immunosuppressive myeloid cells and intra-tumoral macrophages within this therapeutic window may ameliorate mechanisms associated with immunosuppression before and during malignant progression.

IMMU-14. REVEALING THE MANY MYELOID STATES IN HUMAN BRAIN TUMORS AND WAYS TO PERTURB THEM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi94-vi95
Author(s):  
Tyler Miller ◽  
Chadi El Farran ◽  
Julia Verga ◽  
Charles Couturier ◽  
Zeyu Chen ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Human Tumor ◽  
Myeloid Cell ◽  
Low Grade ◽  
Tumor Patients ◽  
The Many

Abstract Recent breakthroughs in immunotherapy have revolutionized treatment for many types of cancer, but unfortunately trials of these therapies have failed to provide meaningful life-prolonging benefit for brain tumor patients, potentially due to abundant immunosuppressive myeloid cells in the tumor. Our ultimate goal is to reprogram immunosuppressive tumor associated myeloid cells to an antitumor state to enable effective immunotherapy. Towards this goal, we have deeply characterized the immune microenvironment of more than 50 primary high and low grade gliomas using high-throughput single-cell RNA-sequencing to reveal recurrent myeloid cell states and immunosuppressive programs across IDH1 wild-type and mutant tumors. We have also established a brain tumor organoid model from primary patient tissue that maintains all of the tumor microenvironment, including myeloid and other immune cells. We utilize the this model to functionally test data-driven reprogramming strategies and understand how they impact the states of tumor and immune cells in the ex vivo human tumor microenvironment.

scholarly journals Distinct Tumor Microenvironments Are a Defining Feature of Strain-Specific CRISPR/Cas9-Induced MPNSTs

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 583 ◽  
Author(s):  
Amanda Scherer ◽  
Victoria R. Stephens ◽  
Gavin R. McGivney ◽  
Wade R. Gutierrez ◽  
Emily A. Laverty ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Mouse Models ◽  
Cancer Biology ◽  
Myeloid Cell ◽  
Inbred Strains ◽  
Peripheral Nerve Sheath Tumors ◽  
Tumor Onset ◽  
The Impact ◽  
Strain Dependent

The tumor microenvironment plays important roles in cancer biology, but genetic backgrounds of mouse models can complicate interpretation of tumor phenotypes. A deeper understanding of strain-dependent influences on the tumor microenvironment of genetically-identical tumors is critical to exploring genotype–phenotype relationships, but these interactions can be difficult to identify using traditional Cre/loxP approaches. Here, we use somatic CRISPR/Cas9 tumorigenesis approaches to determine the impact of mouse background on the biology of genetically-identical malignant peripheral nerve sheath tumors (MPNSTs) in four commonly-used inbred strains. To our knowledge, this is the first study to systematically evaluate the impact of host strain on CRISPR/Cas9-generated mouse models. Our data identify multiple strain-dependent phenotypes, including changes in tumor onset and the immune microenvironment. While BALB/c mice develop MPNSTs earlier than other strains, similar tumor onset is observed in C57BL/6, 129X1 and 129/SvJae mice. Indel pattern analysis demonstrates that indel frequency, type and size are similar across all genetic backgrounds. Gene expression and IHC analysis identify multiple strain-dependent differences in CD4+ T cell infiltration and myeloid cell populations, including M2 macrophages and mast cells. These data highlight important strain-specific phenotypes of genomically-matched MPNSTs that have implications for the design of future studies using similar in vivo gene editing approaches.

scholarly journals Intratumoral interleukin-6 and myeloid cell subsets within the cholangiocarcinoma tumor microenvironment

HPB ◽  
2019 ◽  
Vol 21 ◽  
pp. S7
Author(s):  
M.Y. Zaidi ◽  
M.B. Ware ◽  
A. Krasinskas ◽  
M.R. Farren ◽  
Y. Li ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Interleukin 6 ◽  
Myeloid Cell

scholarly journals Instruction of myeloid cells by the tumor microenvironment: Open questions on the dynamics and plasticity of different tumor-associated myeloid cell populations

2012 ◽  
Vol 1 (7) ◽  
pp. 1135-1145 ◽  
Author(s):  
Elio Schouppe ◽  
Patrick De Baetselier ◽  
Jo A. Van Ginderachter ◽  
Adelaida Sarukhan
Keyword(s):  
Tumor Microenvironment ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Cell Populations ◽  
Open Questions

scholarly journals IM-4 Impact of oHSV activated NOTCH signaling in tumor microenvironment and its impact on anti-tumor immunity

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi7-vi7
Author(s):  
Otani Yoshihiro ◽  
Ji Young Yoo ◽  
Sean E Lawler ◽  
Antonio E Chiocca ◽  
Balveen Kaur
Keyword(s):  
Tumor Microenvironment ◽  
Notch Signaling ◽  
Tumor Immunity ◽  
Myeloid Cell ◽  
Suppressor Cell ◽  
Therapeutic Benefit ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
The Impact ◽  
Recurrent Gbm

Abstract Oncolytic herpes simplex virus-1 (oHSV) is novel FDA-approved immunotherapy for advanced melanoma patients in US. Also, oHSV is recently approved for the treatment of recurrent GBM in Japan. We have shown that oHSV treatment of GBM cells induces NICD cleavage and NOTCH activation in adjacent uninfected glioma cells via HSV-1 microRNA-H16 (Otani Y and Yoo JY, Clin Cancer Res, 2020), however, the consequences of NOTCH on immunotherapy in GBM is unknow. Here we have investigated the impact of oHSV-induced NOTCH signaling on the tumor microenvironment (TME). Analysis of TCGA GBM data and experimental murine models revealed NOTCH induced immunosuppressive myeloid cell recruitment and limited anti-tumor immunity. In oHSV treated tissue, viral infection educated tumor associated macrophages to secrete CCL2 which recruited monocytic myeloid derived suppressor cell (MDSC) that attenuated anti-tumor immunity. Consistent with this, CCL2 induction was also observed in serum of recurrent GBM patients treated with oHSV (NCT03152318). Importantly, blockade of NOTCH signaling reduced the oHSV induced immunosuppressive environment and activated a CD8 dependent anti-tumor memory response. These findings present the opportunities for combination therapies that can help improve therapeutic benefit and anti-tumor immunity in GBM.

scholarly journals ScRNA-seq reveals tumor microenvironment remodeling induced by local intervention-based immunotherapy

2020 ◽  
Author(s):  
Ashley R. Hoover ◽  
Kaili Liu ◽  
Christa I. DeVette ◽  
Jason R. Krawic ◽  
Connor L. West ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Antitumor Immunity ◽  
Tumor Antigens ◽  
Cell Activity ◽  
Myeloid Cell ◽  
Transcriptome Profiling ◽  
Cytokine Signaling ◽  
Activated State ◽  
Laser Immunotherapy

ABSTRACTLaser immunotherapy (LIT) combines local photothermal therapy (PTT), to disrupt tumor homeostasis and release tumor antigens, and an intratumorally administered immunostimulant, N-dihydrogalactochitosan (GC), to induce antitumor immune responses. We performed single-cell RNA sequencing on tumor-infiltrating leukocytes of MMTV-PyMT mouse mammary tumors to characterize LIT-induced myeloid and lymphoid compartment remodeling. Analysis of 49,380 single cell transcriptomes from different treatment groups revealed that proinflammatory IFNα, IFNγ, and TNFα cytokine signaling pathways were enriched in both lymphoid and myeloid cells isolated from LIT-treated tumors. The CD4+ and CD8+ T cells in LIT treated tumors resided in an activated state while immune cells in untreated and PTT-treated tumors remained in a neutral/resting state. Additionally, monocytes recruited into the LIT-treated tumors were driven towards proinflammatory M1-like macrophage phenotypes or monocyte-derived dendritic cells. Our results reveal that LIT prompts immunological remodeling of the tumor microenvironment by initiating broad proinflammatory responses to drive antitumor immunity.STATEMENT OF SIGNIFICANCETranscriptome profiling of tumor infiltrating leukocytes revealed that localized laser immunotherapy (LIT) greatly enhanced antitumor T cell activity by promoting proinflammatory myeloid cell responses within the tumor microenvironment. This manuscript demonstrates that LIT broadly stimulates antitumor immunity and has great potential to synergize with current immunotherapies to increase their efficacy.

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