scholarly journals Formation of the Immunosuppressive Microenvironment of Classic Hodgkin Lymphoma and Therapeutic Approaches to Counter It

2019 ◽  
Vol 20 (10) ◽  
pp. 2416 ◽  
Author(s):  
Donatella Aldinucci ◽  
Cinzia Borghese ◽  
Naike Casagrande
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
T Cell Exhaustion ◽  
Normal Cells ◽  
Cell Exhaustion ◽  
Classic Hodgkin Lymphoma

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed–Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They evade antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation and “educate” (i.e. reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies are being developed to target not only tumor cells but also the tumor microenvironment. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.

scholarly journals The Immunosuppressive Microenvironment of Classic Hodgkin Lymphoma and Therapeutic Approaches to Counter It

2019 ◽  
Author(s):  
Donatella Aldinucci ◽  
Cinzia Borghese ◽  
Naike Casagrande
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
T Cell Exhaustion ◽  
Normal Cells ◽  
Cell Exhaustion ◽  
Classic Hodgkin Lymphoma

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed-Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They are invisible to antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation, and “educate” (i.e., reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies, targeting not only tumor cells but also the tumor microenvironment, are being developed. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become protective or immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.

scholarly journals A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment

2018 ◽  
Vol 6 (1) ◽  
Author(s):  
Yu-Tzu Liu ◽  
Tai-Chung Tseng ◽  
Ruey-Shyang Soong ◽  
Chun-Yi Peng ◽  
Yu-Hsing Cheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

scholarly journals 644 Tumor-mediated suppressive signaling and hypoxia supports altered chromatin landscapes that limit the transcriptional and functional potential of terminal T cell exhaustion

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A673-A673
Author(s):  
Rhodes Ford ◽  
Natalie Rittenhouse ◽  
Nicole Scharping ◽  
Paolo Vignali ◽  
Greg Delgoffe ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Histone Modifications ◽  
Cd8 T Cells ◽  
Tumor Hypoxia ◽  
T Cell Subsets ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

BackgroundCD8+ T cells are a fundamental component of the anti-tumor response; however, tumor-infiltrating CD8+ T cells (TIL) are rendered dysfunctional by the tumor microenvironment. CD8+ TIL display an exhausted phenotype with decreased cytokine expression and increased expression of co-inhibitory receptors (IRs), such as PD-1 and Tim-3. The acquisition of IRs mark the progression of dysfunctional TIL from progenitors (PD-1Low) to terminally exhausted (PD-1+Tim-3+). How the chromatin landscape changes during this progression has not been described.MethodsUsing a low-input ChIP-based assay called Cleavage Under Targets and Release Using Nuclease (CUT&RUN), we have profiled the histone modifications at the chromatin of tumor-infiltrating CD8+ T cell subsets to better understand the relationship between the epigenome and the transcriptome as TIL progress towards terminal exhaustion.ResultsWe have identified two epigenetic characteristics unique to terminally exhausted cells. First, we have identified a unique set of genes, characterized by active histone modifications that do not have correlated gene expression. These regions are enriched for AP-1 transcription factor motifs, yet most AP-1 family factors are actively downregulated in terminally exhausted cells, suggesting signals that promote downregulation of AP-1 expression negatively impacts gene expression. We have shown that inducing expression of AP-1 factors with a 41BB agonist correlates with increased expression of these anticorrelated genes. We have also found a substantial increase in the number of genes that exhibit bivalent chromatin marks, defined by the presence of both active (H3K4me3) and repressive (H3K27me3) chromatin modifications that inhibit gene expression. These bivalent genes in terminally exhausted T cells are not associated with plasticity and represent aberrant hypermethylation in response to tumor hypoxia, which is necessary and sufficient to promote downregulation of bivalent genes.ConclusionsOur study defines for the first time the roles of costimulation and the tumor microenvironment in driving epigenetic features of terminally exhausted tumor-infiltrating T cells. These results suggest that terminally exhausted T cells have genes that are primed for expression, given the right signals and are the basis for future work that will elucidate that factors that drive progression towards terminal T cell exhaustion at the epigenetic level and identify novel therapeutic targets to restore effector function of tumor T cells and mediate tumor clearance.

T‐cell exhaustion interrelates with immune cytolytic activity to shape the inflamed tumor microenvironment

2020 ◽  
Vol 251 (2) ◽  
pp. 147-159 ◽  
Author(s):  
Mei‐Chun Cai ◽  
Xiaojing Zhao ◽  
Min Cao ◽  
Pengfei Ma ◽  
Minjiang Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Cytolytic Activity ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

scholarly journals Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Christof Kaltenmeier ◽  
Hamza O. Yazdani ◽  
Kristin Morder ◽  
David A. Geller ◽  
Richard L. Simmons ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Metastasis ◽  
Neutrophil Extracellular Traps ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Extracellular Traps

While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. Herein, to induce a NET-rich TME, we performed liver Ischemia/Reperfusion (I/R) in an established cancer metastasis model or directly injected NETs in subcutaneous tumors. In this NET-rich TME, the majority of CD4+ and CD8+ tumor infiltrating lymphocytes expressed multiple inhibitory receptors, in addition these cells showed a functional and metabolic exhausted phenotype. Targeting of NETs in vivo by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells. In vitro, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion and dysfunction; an effect abrogated by using PD-L1 KO NETs or culturing NETs with PD-1 KO T cells. Furthermore, we found elevated levels of sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. Neutrophils isolated from patients after surgery were primed to form NETs and induced exhaustion and dysfunction of human CD4+ and CD8+ T cells. We next targeted PD-L1 in vivo by injecting a blocking antibody during liver I/R. A single dose of anti-PD-L1 during surgery lead to diminished tumors at 3 weeks and functional T cells in the TME. Our data thus reveal that NETs have the capability of suppressing T cell responses through metabolic and functional exhaustion and thereby promote tumor growth. Furthermore, targeting of PD-L1 containing NETs at time of surgery with DNAse or anti-PD-L1 lead to diminished tumor growth, which represents a novel and viable strategy for sustaining immune competence within the TME.

scholarly journals The expression of class II major histocompatibility molecules on breast tumors delays T cell exhaustion, expands the T cell repertoire and slows tumor growth

2018 ◽  
Author(s):  
Tyler R. McCaw ◽  
Mei Li ◽  
Dmytro Starenki ◽  
Sara J. Cooper ◽  
Selene Meza-Perez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
T Cell Exhaustion ◽  
Major Histocompatibility ◽  
Cell Exhaustion ◽  
Mhcii Expression

AbstractThe expression of major histocompatibility complex II (MHCII) on tumor cells correlates with survival and responsiveness to immunotherapy. However, the mechanisms underlying these observations are poorly defined. Using a murine breast tumor line, we tested how MHCII expression affected anti-tumor immunity. We found that MHCII-expressing tumors grew more slowly than controls and recruited more functional CD4+ and CD8+ T cells. Additionally, MHCII-expressing tumors contained more TCR clonotypes expanded to a larger degree than control tumors. Functional CD8+ T cells in tumors depended on CD4+ T cells. However, both CD4+ and CD8+ T cells eventually became exhausted, even in MHCII-expressing tumors. PD1 blockade had no impact on tumor growth, potentially because tumor cells poorly expressed PD-L1. These results suggest tumor cell expression of MHCII facilitates the local activation of CD4+ T cells and indirectly helps the activation and expansion of CD8+ T cells, but by itself, cannot prevent T cell exhaustion.PrécisThe expression of MHCII on tumor cells augments CD4 and CD8 T cell responses, expands the TCR repertoire and delays exhaustion. Hence, strategies to induce MHCII expression may be a powerful adjuvant to immunotherapeutic regimens of solid tumors.

scholarly journals IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma

2012 ◽  
Vol 122 (4) ◽  
pp. 1271-1282 ◽  
Author(s):  
Zhi-Zhang Yang ◽  
Deanna M. Grote ◽  
Steven C. Ziesmer ◽  
Toshiro Niki ◽  
Mitsuomi Hirashima ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Non Hodgkin Lymphoma
Sign in / Sign up

Export Citation Format

Share Document