Indoleamine 2,3-dioxygenase and regulatory T cells in acute myeloid leukemia

Mansour, Iman; Zayed, Rania A.; Said, Fadwa; Latif, Lamyaa Abdel

doi:10.1080/10245332.2015.1106814

Cited by 39 publications

(38 citation statements)

References 47 publications

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“…A positive correlation was found between high IDO1 expression in bone marrow-derived mesenchymal stem cells and elevated percentage of T reg cells in acute myeloid leukemia [69]. Therefore, the proportion of CD4 + CD25 + CD39 + T reg cells was analyzed in PMBCs at baseline, during and after BCG therapy.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer

Pichler

Gruenbacher

Čulig

et al. 2016

Cancer Immunol Immunother

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Th1-type immunity is considered to be required for efficient response to BCG in bladder cancer, although Th2 predisposition of BCG responders has recently been reported. The aim was to evaluate the relationship of Th1 and Th2 components in 23 patients undergoing BCG treatment. Peripheral blood, serum and urine samples were prospectively collected at baseline, during and after BCG. Th1 (neopterin, tryptophan, kynurenine, kynurenine-to-tryptophan ratio (KTR), IL-12, IFN-γ, soluble TNF-R75 and IL-2Rα) and Th2 (IL-4, IL-10) biomarkers as well as CD4 expression in T helper (Th), effector and regulatory T cells were determined. Local immune cell subsets were measured on formalin-fixed, paraffin-embedded cancer tissue by immunohistochemistry to examine expression of transcription factors that control Th1 (T-bet) and Th2-type (GATA3) immunity. We confirmed a Th2 predisposition with a mean GATA3/T-bet ratio of 5.51. BCG responders showed significantly higher levels of urinary (p = 0.003) and serum neopterin (p = 0.012), kynurenine (p = 0.015), KTR (p = 0.005), IFN-γ (p = 0.005) and IL-12 (p = 0.003) during therapy, whereas levels of IL-10 decreased significantly (p < 0.001) compared to non-responders. GATA3/T-bet ratio correlated positively with serum neopterin (p = 0.008), IFN-γ (p = 0.013) and KTR (p = 0.018) after the first BCG instillation. We observed a significant increase in CD4 expression in the Th cell population (p < 0.05), with only a modest tendency toward higher frequency in responders compared to non-responders (p = 0.303). The combined assessment of GATA3/T-bet ratio, neopterin and KTR may be a useful biomarker in predicting BCG response. Th2-promoting factors such as GATA3 may trigger Th1-type immune responses and thus contribute to the BCG success.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-016-1945-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer

Pichler

Gruenbacher

Čulig

et al. 2016

Cancer Immunol Immunother

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“…Mesenchymal stem cells (MSCs) are stromal cells which define the bone marrow microenvironment and give rise to other supporting cells. MSCs highly express IDO, which correlates with expansion of Tregs and could inhibit CAR T cell effector function (117).…”

Section: Bone Marrow Nichementioning

confidence: 99%

A Bump in the Road: How the Hostile AML Microenvironment Affects CAR T Cell Therapy

Epperly

Velasquez

2020

Front. Oncol.

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Chimeric antigen receptor (CAR) T cells targeting CD19 have been successful treating patients with relapsed/refractory B cell acute lymphoblastic leukemia (ALL) and B cell lymphomas. However, relapse after CAR T cell therapy is still a challenge. In addition, preclinical and early clinical studies targeting acute myeloid leukemia (AML) have not been as successful. This can be attributed in part to the presence of an AML microenvironment that has a dampening effect on the antitumor activity of CAR T cells. The AML microenvironment includes cellular interactions, soluble environmental factors, and structural components. Suppressive immune cells including myeloid derived suppressor cells and regulatory T cells are known to inhibit T cell function. Environmental factors contributing to T cell exhaustion, including immune checkpoints, anti-inflammatory cytokines, chemokines, and metabolic alterations, impact T cell activity, persistence, and localization. Lastly, structural factors of the bone marrow niche, secondary lymphoid organs, and extramedullary sites provide opportunities for CAR T cell evasion by AML blasts, contributing to treatment resistance and relapse. In this review we discuss the effect of the AML microenvironment on CAR T cell function. We highlight opportunities to enhance CAR T cell efficacy for AML through manipulating, targeting, and evading the anti-inflammatory leukemic microenvironment.

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“…Mansour et al [41] High IDO expression in mesenchymal stem cells and increased levels of T-regs play pivotal role in the pathogenesis of AML combination with CY was recommended by them as an effective IDO-positive lymphoma treatment. These findings suggest that inhibition of IDO might offer a therapeutic approach for lymphoma.…”

Section: Ido In Colorectal Cancer (Crc)mentioning

confidence: 99%

“…IDO is involved in immune system regulation. IDO upregulation is associated with poor prognosis in various cancers [20,30,34,35,39,41,43,51] but few studies suggested that increased expression of IDO was linked with favourable prognosis. [19,46] Further studies are required in view of the contradictory findings, to comprehend this complex role of IDO in various cancers.…”

Section: Ido As An Immunotherapeutic Targetmentioning

confidence: 99%

Indoleamine 2,3 Dioxygenase as an Immunotherapeutic Target Brings a New Hope for Cancer Patients

Asghar

Loya

2018

J Cancer Allied Spec

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Therapeutic manipulation of immune system in cancer has been an extensive area of research in the field of oncoimmunology. Immunotherapy helps the immune system to combat against cancer. Tumour cells take an edge of immunosuppressive mechanisms and inhibit antitumour immune responses. Indoleamine 2,3 dioxygenase (IDO) is an immunosuppressive enzyme which is involved in tumour immune escape mechanism in various cancers. IDO can degrade the tryptophan into kynurenines and has an ability to enhance the immune tolerance through mammalian target of rapamycin pathway general control nonderepressible 2 (GCN2) pathway and induction of regulatory T (T-regs) cells. IDO-induced T-regs suppress the local immune responses in the tumour microenvironment and promote metastasis. IDO overexpression in various cancers is associated with poor prognosis. Several preclinical and clinical trials have been proceeding and recommend that IDO inhibitor may be an influential tool against a wide range of cancers. IDO inhibitors as adjuvant therapeutic agents may also have clinical implications. Thus, IDO has the potential to be used as an immunotherapeutic target. This review discusses the promising role of IDO in cancer and its implication in immunotherapy.Key words: Breast cancer, colorectal cancer, haematological malignancies, immunotherapy, indoleamine 2,3-dioxygenase, pancreatic cancer, prostate cancer

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Indoleamine 2,3-dioxygenase and regulatory T cells in acute myeloid leukemia

Abstract: In this study, we revealed an association between high IDO expression in MSCs and elevated levels of Tregs which could have an important role in the pathogenesis of AML, providing immunosuppressive microenvironment.

Cited by 39 publications

References 47 publications

Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer

Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer

A Bump in the Road: How the Hostile AML Microenvironment Affects CAR T Cell Therapy

Indoleamine 2,3 Dioxygenase as an Immunotherapeutic Target Brings a New Hope for Cancer Patients

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