Expression of Immune Checkpoint Receptors on T-Cells and Their Ligands on Leukemia Blasts in Childhood Acute Leukemia

Kang, Sung Han; Hwang, Hyun Ju; Yoo, Jae Won; Kim, Hyery; Choi, Eun Seok; Hwang, Sang‐Hyun; Cho, Young‐Uk; Jang, Seongsoo; Park, Chan‐Jeoung; Im, Ho Joon; Seo, Jong Jin; Kim, Nayoung; Koh, Kyung‐Nam

doi:10.21873/anticanres.13746

Cited by 24 publications

(27 citation statements)

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“…Further studies on lymphoma cells indicated that the BTLA-HVEM pathway participates in the differentiation and inhibition of γδ T cells after exposure to lymphoma cells [ 32 ], suggesting its involvement in lymphomagenesis. In recent work, Kang et al [ 33 ] investigated associations of the expression of immune checkpoint molecules, among others BTLA and HVEM, with prognosis in childhood acute leukemia (AML and ALL). They found a similar expression of BTLA on γδ + T and αβ + T cells from ALL and AML patients as well as healthy controls; however, they noticed a significantly higher expression of HVEM on αβ + T cells in the low-risk group of AML patients as compared to the high-risk group.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Expression of BTLA and CTLA-4 Immune Checkpoint Molecules in Chronic Lymphocytic Leukemia Patients

Karabon

Partyka

Ciszak

et al. 2020

Journal of Immunology Research

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Chronic lymphocytic leukemia (CLL) is characterized by the peripheral accumulation of neoplastic B cells and is frequently complicated by the systemic immunosuppression associated with an impairment in B and T lymphocyte activation. We hypothesized that the expression of immune checkpoint suppressors B and T lymphocyte attenuator (BTLA) and cytotoxic T lymphocyte antigen (CTLA-4) is disturbed in both lymphocyte subpopulations in CLL. The expression of CTLA-4 and BTLA mRNA was determined by real-time PCR, while CTLA-4 protein expression (surface or intracellular) was estimated in BTLA+ lymphocytes by flow cytometry. In CLL patients, we observed a higher gene transcript level of BTLA and CTLA-4 than in healthy individuals in both freshly isolated and PMA stimulated B and T cells. Remarkably, lower amounts of both inhibitory proteins were found in peripheral blood (PB) CLL B cells, whereas normal BTLA and elevated CTLA-4 were found in T cells. Consistently, there was a prevalence of CTLA-4+ cells within circulating BTLA+ T cells cells of patients confronting PB healthy cells. After in vitro stimulation, the only change found in CLL patients was a decrease in BTLA expression in B and T lymphocytes. In contrast, healthy lymphocytes responded more vigorously as regards the BTLA and CTLA expression with substantially higher frequency of CD69+ cells under the stimulating condition compared to corresponding cells from the CLL group. Our results indicate that CLL development is associated with the affected expression of BTLA and CTLA-4 checkpoint receptors in PB and its impaired expression might be associated with lowering of the threshold for B cell activation and proliferation, while upregulated CTLA-4 expression in CLL peripheral BTLA+ T cells may contribute to suppressed T cell effector functions. This hypothesis needs to be validated in future studies, which would allow us to explain how the increased or decreased expression of these molecules affects the cell function.

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Section: Discussionmentioning

confidence: 99%

Abnormal Expression of BTLA and CTLA-4 Immune Checkpoint Molecules in Chronic Lymphocytic Leukemia Patients

Karabon

Partyka

Ciszak

et al. 2020

Journal of Immunology Research

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“…Increased CTLA-4 expression was also confirmed in various subsets of peripheral T cells in pediatric BCP-ALL. Interestingly, the levels of this checkpoint molecule were more pronounced in high risk ALL subtypes and correlated with decreased relapse-free survival [7].…”

Section: Immune Checkpoints and Their Ligandsmentioning

confidence: 99%

“…There is also growing evidence that natural killer (NK) cells play a role in the immunosurveillance of ALL [4]. However, developing leukemia impairs the key components of the immune system responsible for mounting an anticancer response, particularly in patients poorly responding to treatment or at the relapse stage [5][6][7]. Cancer cells can avoid recognition and elimination by the immune system by various, cancer type-specific mechanisms, which are already well documented in solid tumors and are just being discovered in ALL.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

Pastorczak

Domka

Fidyt

et al. 2021

Cancers

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Acute lymphoblastic leukemia (ALL) results from a clonal expansion of abnormal lymphoid progenitors of B cell (BCP-ALL) or T cell (T-ALL) origin that invade bone marrow, peripheral blood, and extramedullary sites. Leukemic cells, apart from their oncogene-driven ability to proliferate and avoid differentiation, also change the phenotype and function of innate and adaptive immune cells, leading to escape from the immune surveillance. In this review, we provide an overview of the genetic heterogeneity and treatment of BCP- and T-ALL. We outline the interactions of leukemic cells in the bone marrow microenvironment, mainly with mesenchymal stem cells and immune cells. We describe the mechanisms by which ALL cells escape from immune recognition and elimination by the immune system. We focus on the alterations in ALL cells, such as overexpression of ligands for various inhibitory receptors, including anti-phagocytic receptors on macrophages, NK cell inhibitory receptors, as well as T cell immune checkpoints. In addition, we describe how developing leukemia shapes the bone marrow microenvironment and alters the function of immune cells. Finally, we emphasize that an immunosuppressive microenvironment can reduce the efficacy of chemo- and immunotherapy and provide examples of preclinical studies showing strategies for improving ALL treatment by targeting these immunosuppressive interactions.

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“…Collectively, the expression of these proteins is low or stable, but temporary, and is sufficient to reduce cytokine production, proliferation and survival of γδ T cells ( 205 , 206 , 208 , 210 , 211 ). These changes can also be observed in leukemia, as γδ T cells increase the expression of PD1, CTLA4 and BTLA, while LCs strongly regulate the expression of their ligands, such as PD-L1, CD80 and/or CD86, and herpesvirus-entry mediator (HVEM), respectively ( 212 ). This represents an important barrier, as these molecules can prevent the efficient activation of γδ T cells and the associated antitumor response.…”

Section: Harnessing γδ T Cells Against Leukemia: From Marrow To Bloodmentioning

confidence: 99%

γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

et al. 2021

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Recently, many discoveries have elucidated the cellular and molecular diversity in the leukemic microenvironment and improved our knowledge regarding their complex nature. This has allowed the development of new therapeutic strategies against leukemia. Advances in biotechnology and the current understanding of T cell-engineering have led to new approaches in this fight, thus improving cell-mediated immune response against cancer. However, most of the investigations focus only on conventional cytotoxic cells, while ignoring the potential of unconventional T cells that until now have been little studied. γδ T cells are a unique lymphocyte subpopulation that has an extensive repertoire of tumor sensing and may have new immunotherapeutic applications in a wide range of tumors. The ability to respond regardless of human leukocyte antigen (HLA) expression, the secretion of antitumor mediators and high functional plasticity are hallmarks of γδ T cells, and are ones that make them a promising alternative in the field of cell therapy. Despite this situation, in particular cases, the leukemic microenvironment can adopt strategies to circumvent the antitumor response of these lymphocytes, causing their exhaustion or polarization to a tumor-promoting phenotype. Intervening in this crosstalk can improve their capabilities and clinical applications and can make them key components in new therapeutic antileukemic approaches. In this review, we highlight several characteristics of γδ T cells and their interactions in leukemia. Furthermore, we explore strategies for maximizing their antitumor functions, aiming to illustrate the findings destined for a better mobilization of γδ T cells against the tumor. Finally, we outline our perspectives on their therapeutic applicability and indicate outstanding issues for future basic and clinical leukemia research, in the hope of contributing to the advancement of studies on γδ T cells in cancer immunotherapy.

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Expression of Immune Checkpoint Receptors on T-Cells and Their Ligands on Leukemia Blasts in Childhood Acute Leukemia

Cited by 24 publications

References 0 publications

Abnormal Expression of BTLA and CTLA-4 Immune Checkpoint Molecules in Chronic Lymphocytic Leukemia Patients

Abnormal Expression of BTLA and CTLA-4 Immune Checkpoint Molecules in Chronic Lymphocytic Leukemia Patients

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

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