Leukemia-induced dysfunctional TIM-3+CD4+ bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients

Blaeschke, Franziska; Willier, Semjon; Stenger, Dana; Lepenies, Mareike; Horstmann, Martin; Escherich, Gabriele; Zimmermann, Martin; Ringeling, Francisca Rojas; Canzar, Stefan; Kaeuferle, Theresa; Rohlfs, Meino; Binder, Vera; Klein, Christoph; Feuchtinger, Tobias

doi:10.1038/s41375-020-0793-1

Cited by 33 publications

(38 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other inhibitory interactions involving leukemic T cells, such as PD-1/PD-L1, TIM-3/galectin-9, TIGIT/CD155, and their effects on the immune anti-leukemic responses were recently described [3,5,158]. For instance, in a syngeneic murine BCP-ALL leukemia model, the PD-1 level was increased in CD4 + and CD8 + T cells, and, to some extent, ALLinduced PD-1 expression was independent of TCR activation [159].…”

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%

“…Downregulation or loss of human leukocyte antigen (HLA) class I molecules, which leads to impaired recognition of leukemic cells by cytotoxic T lymphocytes, is a rare but functionally significant mechanism of immune evasion in ALL [8]. Moreover, recent data uncovers the mechanism of T cell exhaustion operating in ALL [5,9,10], opening the possibility to employ appropriate immune checkpoint inhibitors to ALL treatment protocols. Finally, novel, high-throughput methods, in particular single cell RNA sequencing, reveal the important role of suppressive myeloid cell populations in promoting leukemia progression and hampering treatment efficacy [11].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

Pastorczak

Domka

Fidyt

et al. 2021

Cancers

View full text Add to dashboard Cite

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.

show abstract

Section: Immune Checkpoints and Their Ligandsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

Pastorczak

Domka

Fidyt

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“… 1 2 Mechanisms of immune escape have been either loss of target structure or insufficient CAR T-cell persistence in vivo. 3 4 Here, we report a novel clinical presentation of BCP-ALL relapse under CAR T-cell therapy, relapse within the eye as an immunologically privileged organ. CD19-CAR T cells are currently evaluated in numerous clinical trials 5 and especially pediatric BCP-ALL shows initial response rates to CD19-CAR T cells of more than 80% in refractory or relapsed, heavily pretreated patients.…”

Section: Introductionmentioning

confidence: 92%

Leukemia escape in immune desert: intraocular relapse of pediatric pro-B-ALL during systemic control by CD19-CAR T cells

Willier¹,

Raedler²,

Blaeschke³

et al. 2020

J Immunother Cancer

Self Cite

View full text Add to dashboard Cite

BackgroundRelapsed/refractory B-precursor acute lymphoblastic leukemia (BCP-ALL) remains a major therapeutic challenge in pediatric hematology. Chimeric antigen receptor (CAR) T cells targeting CD19 have shown remarkable initial response rates in BCP-ALL patients, while long-term leukemia control rate is only about 50%. So far, main mechanisms of BCP-ALL relapse after CD19-CAR T-cell therapy have been either insufficient CAR T-cell persistence in vivo or loss of surface CD19.Case ReportHere, we report an exceptional presentation of BCP-ALL relapse in the eye during the systemic control through CAR T-cell therapy. We report a case of fatal intraocular relapse in a pediatric patient with pro-B-ALL after initial response to CD19-CAR T-cell therapy. One month after CD19-CAR T-cell therapy, remission was documented by bone marrow aspirate analysis with absence of CD19+ cells and CD19-CAR T cells could be detected in both peripheral blood and bone marrow. At the same time, however, the patient presented with progressive visual disturbance and CD19+ cells were found within the anterior chamber of the eye. Despite local and systemic therapy, ocular relapse led to BCP-ALL dissemination and systemic relapse within weeks. The eye represents a rare site for local manifestation of BCP-ALL, but isolated intraocular relapse is a clinically unreckoned presentation of BCP-ALL in the era of CD19-CAR T cells.ConclusionDuring systemic control of BCP-ALL through CD19-CAR T cells, relapse can emerge in the eye as an immune-privileged organ. Ocular symptoms after CD19-CAR T-cell therapy should guide the clinician to elucidate the etiology in a timely fashion in order to adjust leukemia treatment strategy. Both, local immune escape as well as insufficient CAR T-cell persistence may have contributed to relapse in the reported patient. Mechanisms of relapse in an immune desert under CAR T-cell therapy require future clinical and experimental attention. In particular, ocular symptoms after CAR T-cell therapy should be considered a potentially early sign of leukemia relapse.

show abstract

“…In acute B lymphoblastic leukemia, increased expression of both TIM-3 and PD-1 on CD4 + and CD8 + T cells has been observed following relapse after stem cell transplant [106]. Additionally, CD200/TIM-3 signaling has been implicated in T-cell dysfunction in pediatric B-precursor acute lymphoblastic leukemia, with expression of TIM-3 on CD4+ bone marrow T cells being associated with increased risk of relapse [107]. Conversely, however, immune checkpoint inhibition in early chronic lymphocytic leukemia may not reverse exhaustion of CD8 + T cells [108], and TIM-3 does not appear to be widely expressed in peripheral T-cell lymphomas [109].…”

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

View full text Add to dashboard Cite

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.

show abstract

Leukemia-induced dysfunctional TIM-3+CD4+ bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients

Cited by 33 publications

References 43 publications

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

Leukemia escape in immune desert: intraocular relapse of pediatric pro-B-ALL during systemic control by CD19-CAR T cells

TIM-3 pathway dysregulation and targeting in cancer

Contact Info

Product

Resources

About