T cell exhaustion and a failure in antigen presentation drive resistance to the graft-versus-leukemia effect

Zhou, Meng; Sacirbegovic, Faruk; Zhao, Kai; Rosenberger, Sarah; Shlomchik, Warren D.

doi:10.1038/s41467-020-17991-y

Cited by 33 publications

(21 citation statements)

References 64 publications

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“…It might be related with the large number of lymphoma cells in developing the GVT models. The onset of aGVHD in GVT mouse model might be delayed or did not occur, because the large amount of tumor cells could result in T cell exhaustion 39 , 40 .…”

Section: Discussionmentioning

confidence: 99%

Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease

Sun

Yang

et al. 2021

Cell Transplant

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Acute graft-versus-host disease (aGVHD) is one of the most common complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Janus kinase (JAK) inhibitors are considered as reliable and promising agents for patients with aGVHD. The prophylactic and therapeutic effects of SHR0302, a novel JAK inhibitor, were evaluated in aGVHD mouse models. The overall survival (OS), progression-free survival (PFS), bodyweight of mice, GVHD scores were observed and recorded. The bone marrow and spleen samples of diseased model mice or peripheral blood of patients were analyzed. SHR0302 could prevent and reverse aGVHD in mouse models with preserving graft-versus-tumor effect. Functionally, SHR0302 improved the OS and PFS, restored bodyweight, reduced GVHD scores, and reduced immune cells infiltrated in target tissues. SHR0302 treatment also enhanced the hematopoietic reconstruction compared to the control group. Mechanistically, our results suggested that SHR0302 could inhibit the activation of T cells and modulate the differentiation of helper T (Th) cells by reducing Th1 and increasing regulatory T (Treg) cells. In addition, SHR0302 decreased the expression of chemokine receptor CXCR3 on donor T cells and the secretion of cytokines or chemokines including interleukin (IL)-6, interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), CXCL10, etc. thereby destroying the IFN-γ/CXCR3/CXCL10 axis which promotes the progression of GVHD. Besides, SHR0302 decreased the phosphorylation of JAK and its downstream STATs, AKT and ERK1/2, which ultimately regulated the activation, proliferation, and differentiation of lymphocytes. Experiments on primary cells from aGVHD patients also confirmed the results. In summary, our results indicated that JAK inhibitor SHR0302 might be used as a novel agent for patients with aGVHD.

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Section: Discussionmentioning

confidence: 99%

Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease

Sun

Yang

et al. 2021

Cell Transplant

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“…The only randomized clinical trial of checkpoint inhibition in myeloid malignancies combined the anti-PD-L1 antibody durvalumab with azacitidine as frontline therapy in patients with higher-risk MDS and in older patients with AML unfit for intensive chemotherapy; no improvements were reported in response rate or survival compared with the results of azacitidine monotherapy in either cohort [89]. Notably, however, PD-1 blockade following stem cell transplant in AML may enhance the graft-versusleukemia effect and T-cell function [90]. Although it is clear that immuno-oncologic therapeutics have not yet revolutionized the hematologic malignancy treatment landscape as in solid tumors, the clinical success of stem cell transplant in myeloid malignancies demonstrates the potential of immunotherapeutic modalities in these diseases in particular [13,[91][92][93].…”

Section: Targeting Tim-3 In Myeloid Malignanciesmentioning

confidence: 99%

TIM-3 pathway dysregulation and targeting in cancer

Zeidan

Komrokji

Brunner

2021

Expert Review of Anticancer Therapy

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Introduction: Dysfunction of the immune system is a hallmark of cancer. Through increased understanding of the complex interactions between immunity and cancer, immunotherapy has emerged as a treatment modality for different types of cancer. Promising activity with immunotherapy has been reported in numerous malignancies, but challenges such as limited response rates and treatment resistance remain. Furthermore, outcomes with this therapeutic approach in hematologic malignancies are even more limited than in solid tumors. T-cell immunoglobulin domain and mucin domain 3 (TIM-3) has emerged as a potential immune checkpoint target in both solid tumors and hematologic malignancies. TIM-3 has been shown to promote immune tolerance, and overexpression of TIM-3 is associated with more aggressive or advanced disease and poor prognosis.Areas covered: This review examines what is currently known regarding the biology of TIM-3 and clinical implications of targeting TIM-3 in cancer. Particular focus is given to myeloid malignancies. Expert opinion: The targeting of TIM-3 is a promising therapeutic approach in cancers, including hematologic cancers such as myeloid malignancies which have not benefited much from current immunotherapeutic treatment approaches. We anticipate that with further clinical evaluation, TIM-3 blockade will emerge as an important treatment strategy in myeloid malignancies.

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“…A recent study assessed the mechanisms of GVL failure using an elegant mouse model, in which GVL is exclusively mediated by alloreactive CD8 + T cells recognizing the MiHA H60, making it possible to specifically track and analyze the GVL-inducing T cells ( 55 , 56 ). Next to insufficient H60 presentation, the GVL effect in this model failed due to the development of leukemia-specific T cell exhaustion, characterized by expression of the inhibitory receptors PD-1, TIGIT, LAG3, and TIM3 and the transcription factor TOX, which has recently been shown to drive T cell exhaustion ( 57 – 61 ).…”

Section: Immune Checkpoints and Relapse After Allo-hctmentioning

confidence: 99%

“…Next to insufficient H60 presentation, the GVL effect in this model failed due to the development of leukemia-specific T cell exhaustion, characterized by expression of the inhibitory receptors PD-1, TIGIT, LAG3, and TIM3 and the transcription factor TOX, which has recently been shown to drive T cell exhaustion ( 57 – 61 ). Blockade of PD-1 was able to reverse the T cell exhaustion phenotype and restore the GVL effect, whereas blockade of TIM3, LAG3, and TIGIT were not, suggesting that PD-1 may be the dominant inhibitory checkpoint contributing to GVL failure in mice ( 55 ).…”

Section: Immune Checkpoints and Relapse After Allo-hctmentioning

confidence: 99%

The Role of Immune Checkpoint Molecules for Relapse After Allogeneic Hematopoietic Cell Transplantation

et al. 2021

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Immune checkpoint molecules represent physiological brakes of the immune system that are essential for the maintenance of immune homeostasis and prevention of autoimmunity. By inhibiting these negative regulators of the immune response, immune checkpoint blockade can increase anti-tumor immunity, but has been primarily successful in solid cancer therapy and Hodgkin lymphoma so far. Allogeneic hematopoietic cell transplantation (allo-HCT) is a well-established cellular immunotherapy option with the potential to cure hematological cancers, but relapse remains a major obstacle. Relapse after allo-HCT is mainly thought to be attributable to loss of the graft-versus-leukemia (GVL) effect and hence escape of tumor cells from the allogeneic immune response. One potential mechanism of immune escape from the GVL effect is the inhibition of allogeneic T cells via engagement of inhibitory receptors on their surface including PD-1, CTLA-4, TIM3, and others. This review provides an overview of current evidence for a role of immune checkpoint molecules for relapse and its treatment after allo-HCT, as well as discussion of the immune mediated side effect graft-vs.-host disease. We discuss the expression of different immune checkpoint molecules on leukemia cells and T cells in patients undergoing allo-HCT. Furthermore, we review mechanistic insights gained from preclinical studies and summarize clinical trials assessing immune checkpoint blockade for relapse after allo-HCT.

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T cell exhaustion and a failure in antigen presentation drive resistance to the graft-versus-leukemia effect

Cited by 33 publications

References 64 publications

Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease

Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease

TIM-3 pathway dysregulation and targeting in cancer

The Role of Immune Checkpoint Molecules for Relapse After Allogeneic Hematopoietic Cell Transplantation

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