scholarly journals T-cell dysfunction in chronic lymphocytic leukemia from an epigenetic perspective

Haematologica ◽  
2021 ◽  
Author(s):  
Fleur S. Peters ◽  
Jonathan C. Strefford ◽  
Eric Eldering ◽  
Arnon P. Kater
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Lymphocytic Leukemia ◽  
T Cell Therapy ◽  
High Expectations ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Cellular immunotherapeutic approaches such as chimeric antigen receptor (CAR) T-cell therapy in chronic lymphocytic leukemia (CLL) thus far have not met the high expectations. Therefore it is essential to better understand the molecular mechanisms of CLLinduced T-cell dysfunction. Even though a significant number of studies are available on T-cell function and dysfunction in CLL patients, none examine dysfunction at the epigenomic level. In non-malignant T-cell research, epigenomics is widely employed to define the differentiation pathway into T-cell exhaustion. Additionally, metabolic restrictions in the tumor microenvironment that cause T-cell dysfunction are often mediated by epigenetic changes. With this review paper we argue that understanding the epigenetic (dys)regulation in T cells of CLL patients should be leveled to the knowledge we currently have of the neoplastic B cells themselves. This will permit a complete understanding of how these immune cell interactions regulate T- and B-cell function. Here we relate the cellular and phenotypic characteristics of CLL-induced T-cell dysfunction to epigenetic studies of T-cell regulation emerging from chronic viral infection and tumor models. This paper proposes a framework for future studies into the epigenetic regulation of CLL-induced Tcell dysfunction, knowledge that will help to guide improvements in the utility of autologous T-cell based therapies in CLL.

scholarly journals The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia

Haematologica ◽  
2013 ◽  
Vol 98 (6) ◽  
pp. 953-963 ◽  
Author(s):  
D. Brusa ◽  
S. Serra ◽  
M. Coscia ◽  
D. Rossi ◽  
G. D'Arena ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

scholarly journals Hematopoietic versus Solid Cancers and T Cell Dysfunction: Looking for Similarities and Distinctions

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 284
Author(s):  
Chiara Montironi ◽  
Cristina Muñoz-Pinedo ◽  
Eric Eldering
Keyword(s):  
T Cell ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
T Cell Therapy ◽  
Cell Dysfunction ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
T Cell Dysfunction ◽  
Cancer Types

Cancer cells escape, suppress and exploit the host immune system to sustain themselves, and the tumor microenvironment (TME) actively dampens T cell function by various mechanisms. Over the last years, new immunotherapeutic approaches, such as adoptive chimeric antigen receptor (CAR) T cell therapy and immune checkpoint inhibitors, have been successfully applied for refractory malignancies that could only be treated in a palliative manner previously. Engaging the anti-tumor activity of the immune system, including CAR T cell therapy to target the CD19 B cell antigen, proved to be effective in acute lymphocytic leukemia. In low-grade hematopoietic B cell malignancies, such as chronic lymphocytic leukemia, clinical outcomes have been tempered by cancer-induced T cell dysfunction characterized in part by a state of metabolic lethargy. In multiple myeloma, novel antigens such as BCMA and CD38 are being explored for CAR T cells. In solid cancers, T cell-based immunotherapies have been applied successfully to melanoma and lung cancers, whereas application in e.g., breast cancer lags behind and is modestly effective as yet. The main hurdles for CAR T cell immunotherapy in solid tumors are the lack of suitable antigens, anatomical inaccessibility, and T cell anergy due to immunosuppressive TME. Given the wide range of success and failure of immunotherapies in various cancer types, it is crucial to comprehend the underlying similarities and distinctions in T cell dysfunction. Hence, this review aims at comparing selected, distinct B cell-derived versus solid cancer types and at describing means by which malignant cells and TME might dampen T cell anti-tumor activity, with special focus on immunometabolism. Drawing a meaningful parallel between the efficacy of immunotherapy and the extent of T cell dysfunction will shed light on areas where we can improve immune function to battle cancer.

scholarly journals Dynamic Expressions of TIGIT on Splenic T Cells and TIGIT-Mediated Splenic T Cell Dysfunction of Mice With Chronic Toxoplasma gondii Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Haoran Li ◽  
Jing Zhang ◽  
Changwei Su ◽  
Xiaowei Tian ◽  
Xuefang Mei ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Cell Function ◽  
Immune Cell ◽  
Rt Pcr ◽  
Cell Dysfunction ◽  
T Cell Dysfunction ◽  
Toxoplasma Gondii Infection ◽  
Cellular Immune

As an immunosuppressive receptor, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) play a critical part in cellular immune regulation mediated by pathogen infection. Whereas, TIGIT expression on splenic T cells in hosts infected with Toxoplasma gondii cysts has not been studied. In this study, we detected TIGIT expression and the changes of immune function in the spleen by flow cytometry and real-time PCR (RT-PCR). We found that TIGIT expression on splenic T cells increased significantly post infection. At the same time, splenic TIGIT+TCM cells were activated and transformed into TIGIT+TEM cells during the infection, and the cytotoxicity of TIGIT+ T cells was reduced in the later stage of infection. This study shows that chronic T. gondii infection can upregulate TIGIT expression on the surface of T cells and affect immune cell function.

scholarly journals E -TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction

2009 ◽  
Vol 106 (15) ◽  
pp. 6250-6255 ◽  
Author(s):  
G. Gorgun ◽  
A. G. Ramsay ◽  
T. A. W. Holderried ◽  
D. Zahrieh ◽  
R. Le Dieu ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

scholarly journals A Phase II Trial of Ibrutinib and PD-1 Blockade in Asymptomatic High Risk Chronic Lymphocytic Leukemia to Improve Immune Function

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5483-5483
Author(s):  
Julio C. Chavez ◽  
Ariel F Grajales-Cruz ◽  
Virginia Olivia Volpe ◽  
Elyce P. Turba ◽  
Lisa Nodzon ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Immune Responses ◽  
Board Of Directors ◽  
Unmet Need ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Background: Chronic lymphocytic leukemia (CLL) is the most common chronic leukemia. Patients in active surveillance with untreated high-risk CLL (defined as presence of del17p or TP53, del11q or ATM mutation or unmutated IGVH) have an unmet need as they tend to progress rapidly and develop resistance to standard therapies. There is evidence that deferring treatment in high-risk patients may be detrimental due to a more aggressive course of disease and that patients with clonal evolution into high-risk features may fare even worse prognosis (Shanafelt et al, JCO 2006). The CLL12 trial (ibrutinib for asymptomatic high risk CLL patients, Langerbeins et al ICML2019) showed event (EFS) and progression (PFS) free survival benefit when compared to placebo. In addition, T-cell dysfunction and immunosuppressive environment have been shown in CLL. The rationale of the trial is that the combination of PD1:PDL1 Blockade (PDB) and ibrutinib will reverse T cell dysfunction commonly seen in CLL patients, potentiating more robust anti-infective and anti-tumor immune responses. Methods: This is a phase 2 clinical trial. Enrollment goal: 25. Treatment will consist of the combination of pembrolizumab (Pem) 200 mg IV every 3 weeks and ibrutinib 420 mg daily orally (to be started after 2nd infusion of PDB) for up to 51 weeks, as depicted in Figure 1. Eligibility criteria includes: Age > 18, confirmed diagnosis of CLL, presence of at least 1 high risk factor for CLL (Del17p, Del11q and or unmutated IGVH), and not meeting iwCLL criteria to start treatment. Primary endpoints are incidence of complete remission (CR) and time to CLL response. Secondary endpoints: overall response rate (ORR), restoration of immune response (decreased markers of T-cell exhaustion and improvement in quantitative immunoglobulins), safety, PFS. Exploratory biomarkers include evaluation of T-cell and B-cell function and cytokine profile at different time points through therapy. Disclosures Chavez: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Nodzon:Pfizer: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy, Other: Speaker Fees; Abbvie: Other: Speaker Fees. Pinilla Ibarz:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy; TG Therapeutics: Consultancy; Bayer: Speakers Bureau; Sanofi: Speakers Bureau. OffLabel Disclosure: The combination of PD1:PDL1 Blockade (PDB) and ibrutinib will reverse T cell dysfunction commonly seen in CLL patients, potentiating more robust anti-infective and anti-tumor immune responses

scholarly journals Expansion of Monocytic Myeloid-Derived Suppressor Cells Dampens T Cell Function in HIV-1-Seropositive Individuals

2012 ◽  
Vol 87 (3) ◽  
pp. 1477-1490 ◽  
Author(s):  
Aiping Qin ◽  
Weiping Cai ◽  
Ting Pan ◽  
Kang Wu ◽  
Qiong Yang ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Suppressor Cells ◽  
Cell Contact ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Dysfunction ◽  
Arginase 1 ◽  
T Cell Function ◽  
T Cell Dysfunction ◽  
Hiv 1

ABSTRACTT lymphocyte dysfunction contributes to human immunodeficiency virus type 1 (HIV-1) disease progression by impairing antivirus cellular immunity. However, the mechanisms of HIV-1 infection-mediated T cell dysfunction are not completely understood. Here, we provide evidence that expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) suppressed T cell function in HIV-1-infected individuals. We observed a dramatic elevation of M-MDSCs (HLA-DR−/lowCD11b+CD33+/highCD14+CD15−cells) in the peripheral blood of HIV-1-seropositive subjects (n= 61) compared with healthy controls (n= 51), despite efficacious antiretroviral therapy for nearly 2 years. The elevated M-MDSC frequency in HIV-1+subjects correlated with prognostic HIV-1 disease markers, including the HIV-1 load (r= 0.5957;P< 0.0001), CD4+T cell loss (r= −0.5312;P< 0.0001), and activated T cells (r= 0.4421;P= 0.0004). Functional studies showed that M-MDSCs from HIV-1+subjects suppressed T cell responses in both HIV-1-specific and antigen-nonspecific manners; this effect was dependent on the induction of arginase 1 and required direct cell-cell contact. Further investigations revealed that direct HIV-1 infection or culture with HIV-1-derived Tat protein significantly enhanced human MDSC generationin vitro, and MDSCs from healthy donors could be directly infected by HIV-1 to facilitate HIV-1 replication and transmission, indicating that a positive-feedback loop between HIV-1 infection and MDSC expansion existed. In summary, our studies revealed a novel mechanism of T cell dysfunction in HIV-1-infected individuals and suggested that targeting MDSCs may be a promising strategy for HIV-1 immunotherapy.

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