TIM-3 in Leukemia; Immune Response and Beyond

Rezaei, Mahnaz; Tan, Jiaxiong; Zeng, Chengwu; Li, Yangqiu; Ganjalikhani‐Hakemi, Mazdak

doi:10.3389/fonc.2021.753677

Cited by 40 publications

(36 citation statements)

References 89 publications

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“…Despite high initial response rates in B-cell precursor leukemia and lymphoma, anti-CD19 CAR T-cell therapy can lack long-term efficacy due to multiple factors including limited CAR T-cell proliferation and persistence ( 3 , 27 ). In recent work, we and others showed that TIM-3 expression on T cells can limit antileukemic T-cell responses both in terms of cytokine release and proliferation ( 19 , 28 ). Here, we found that TIM-3 gets upregulated on conventional anti-CD19 CAR T cells after a single stimulation with target cells potentially to prevent excessive stimulation.…”

Section: Discussionmentioning

confidence: 99%

Design and Evaluation of TIM-3-CD28 Checkpoint Fusion Proteins to Improve Anti-CD19 CAR T-Cell Function

et al. 2022

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Therapeutic targeting of inhibitory checkpoint molecules in combination with chimeric antigen receptor (CAR) T cells is currently investigated in a variety of clinical studies for treatment of hematologic and solid malignancies. However, the impact of co-inhibitory axes and their therapeutic implication remains understudied for the majority of acute leukemias due to their low immunogenicity/mutational load. The inhibitory exhaustion molecule TIM-3 is an important marker for the interaction of T cells with leukemic cells. Moreover, inhibitory signals from malignant cells could be transformed into stimulatory signals by synthetic fusion molecules with extracellular inhibitory receptors fused to an intracellular stimulatory domain. Here, we designed a variety of different TIM-3-CD28 fusion proteins to turn inhibitory signals derived by TIM-3 engagement into T-cell activation through CD28. In the absence of anti-CD19 CAR, two TIM-3-CD28 fusion receptors with large parts of CD28 showed strongest responses in terms of cytokine secretion and proliferation upon stimulation with anti-CD3 antibodies compared to controls. We then combined these two novel TIM-3-CD28 fusion proteins with first- and second-generation anti-CD19 CAR T cells and found that the fusion receptor can increase proliferation, activation, and cytotoxic capacity of conventional anti-CD19 CAR T cells. These additionally armed CAR T cells showed excellent effector function. In terms of safety considerations, the fusion receptors showed exclusively increased cytokine release, when the CAR target CD19 was present. We conclude that combining checkpoint fusion proteins with anti-CD19 CARs has the potential to increase T-cell proliferation capacity with the intention to overcome inhibitory signals during the response against malignant cells.

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Section: Discussionmentioning

confidence: 99%

Design and Evaluation of TIM-3-CD28 Checkpoint Fusion Proteins to Improve Anti-CD19 CAR T-Cell Function

et al. 2022

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“…Finally, we must conclude with cautionary notes regarding TIM-3 as a target and lactose as a modulator. Encouraging response rates have been reported with anti-TIM-3 antibodies for MDS and AML treatments, but the effect of TIM-3 blockade has been much less promising in patients with chronic lymphocytic leukemia [ 16 ]. TIM-3 is no cure-all for every cancer, and we need to comprehend further the biology of the target [ 197 ].…”

Section: Discussionmentioning

confidence: 99%

“…In AML, studies have shown an overexpression of TIM-3 on leukemia stem cells (LSC) but not on healthy stem cells [ 58 , 59 , 60 ]. The blockade of the receptor induces a direct inhibition of AML cell proliferation and restores T cell function [ 16 ]. Thus, targeting TIM-3 offers a unique opportunity to target the LSC population resistant to chemotherapy and largely implicated in tumor relapse [ 61 ].…”

Section: The Tim-3 Immune Checkpoint and Its Targeting With Antibodiesmentioning

confidence: 99%

“…One of the emerging immune checkpoint molecules is the T-cell immunoglobulin mucin-3 (Tim-3)/Galectin-9 (Gal-9) checkpoint, viewed as a promising target for the treatment of breast cancer, bladder cancer and others [ 11 , 12 , 13 , 14 ]. Blockade of the TIM-3/Gal-9 checkpoint is considered a valid option in hematological malignancies, notably for the treatment of AML and myelodysplastic syndromes [ 15 , 16 , 17 , 18 ]. In the present review, we have analyzed the targeting of the TIM-3/Gal-9 checkpoint with various molecules, small and large, and analyzed specifically the potential benefit of lactose as an immune checkpoint regulator.…”

Section: Introductionmentioning

confidence: 99%

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Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

Bailly

Thuru

Quesnel

2021

Cancers

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The disaccharide lactose is an excipient commonly used in pharmaceutical products. The two anomers, α- and β-lactose (α-L/β-L), differ by the orientation of the C-1 hydroxyl group on the glucose unit. In aqueous solution, a mutarotation process leads to an equilibrium of about 40% α-L and 60% β-L at room temperature. Beyond a pharmaceutical excipient in solid products, α-L has immuno-modulatory effects and functions as a major regulator of TIM-3/Gal-9 immune checkpoint, through direct binding to the β-galactoside-binding lectin galectin-9. The blockade of the co-inhibitory checkpoint TIM-3 expressed on T cells with anti-TIM-3 antibodies represents a promising approach to combat different onco-hematological diseases, in particular myelodysplastic syndromes and acute myeloid leukemia. In parallel, the discovery and development of anti-TIM-3 small molecule ligands is emerging, including peptides, RNA aptamers and a few specifically designed heterocyclic molecules. An alternative option consists of targeting the different ligands of TIM-3, notably Gal-9 recognized by α-lactose. Modulation of the TIM-3/Gal-9 checkpoint can be achieved with both α- and β-lactose. Moreover, lactose is a quasi-pan-galectin ligand, capable of modulating the functions of most of the 16 galectin molecules. The present review provides a complete analysis of the pharmaceutical and galectin-related biological functions of (α/β)-lactose. A focus is made on the capacity of lactose and Gal-9 to modulate both the TIM-3/Gal-9 and PD-1/PD-L1 immune checkpoints in oncology. Modulation of the TIM-3/Gal-9 checkpoint is a promising approach for the treatment of cancers and the role of lactose in this context is discussed. The review highlights the immuno-regulatory functions of lactose, and the benefit of the molecule well beyond its use as a pharmaceutical excipient.

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“…demonstrated that an IDO1-related immune gene signature predicts overall survival in AML ( 64 ). Another target to induce T-cell anergy is T-cell immunoglobulin and mucin domain 3 (TIM3), which binds to and is activated by galectin-9, the latter being highly expressed on AML blasts, which leads to an activation of several downstream signaling pathways such as the MAPK/ERK, PI3K- and AKT ( 65 ). TIM3 can stimulate the production of IDO and thus foster immune evasion ( 66 ).…”

Section: The Role Of Lymphocytes and Monocytes In Aml Immune Escapementioning

confidence: 99%

Tumor Microenvironment in Acute Myeloid Leukemia: Adjusting Niches

Menter

Tzankov

2022

Front. Immunol.

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Acute myeloid leukemias (AML) comprise a wide array of different entities, which have in common a rapid expansion of myeloid blast cells leading to displacement of normal hematopoietic cells and also disruption of the microenvironment in the bone marrow niches. Based on an insight into the complex cellular interactions in the bone marrow niches in non-neoplastic conditions in general, this review delineates the complex relationship between leukemic cells and reactive cells of the tumor microenvironment (TME) in AML. A special focus is directed on niche cells and various T-cell subsets as these also provide a potential therapeutic rationale considering e.g. immunomodulation. The TME of AML on the one hand plays a vital role for sustaining and promoting leukemogenesis but - on the other hand - it also has adverse effects on abnormal blasts developing into overt leukemia hindering their proliferation and potentially removing such cells. Thus, leukemic cells need to and develop strategies in order to manipulate the TME. Interference with those strategies might be of particular therapeutic potential since mechanisms of resistance related to tumor cell plasticity do not apply to it.

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TIM-3 in Leukemia; Immune Response and Beyond

Cited by 40 publications

References 89 publications

Design and Evaluation of TIM-3-CD28 Checkpoint Fusion Proteins to Improve Anti-CD19 CAR T-Cell Function

Design and Evaluation of TIM-3-CD28 Checkpoint Fusion Proteins to Improve Anti-CD19 CAR T-Cell Function

Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

Tumor Microenvironment in Acute Myeloid Leukemia: Adjusting Niches

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