Lenalidomide-based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients

Abstract NK cells play an important role in the reciprocal interaction of tumor cells with the immune system and participate in the surveillance of hematological malignancies including acute myeloid leukemia (AML). Among the molecules influencing host-tumor interaction are many members of the TNF superfamily, which mediate multiple cellular functions including cellular proliferation, differentiation and cell death. The TNF family member Glucocorticoid-induced TNF Receptor (GITR) costimulates effector T cells, modulates apoptosis and nuclear factor kappa B and abrogates suppression of murine but not human regulatory T cells. Its cognate ligand GITRL has been found in various healthy tissues. Recently we reported that NK cells express GITR, while solid tumors express GITR ligand (GITRL), and GITR/GITRL interaction downregulates NK cell cytotoxicity and IFN-γ production. Here we analyzed the role of GITR and its ligand in AML. We report for the first time that GITRL is expressed on primary AML cells in 18 of 30 patients as determined by FACS and RT-PCR analysis. Reverse signaling through GITRL using a recombinant GITR-Ig fusion protein induces the release of the immunoregulatory cytokines IL-10 and TNF as determined by ELISA. GITRL-mediated cytokine production of AML cells is abrogated by inhibition of mitogen activated protein kinase (MAPK) pathways as demonstrated by addition of the specific p38 MAPK inhibitor SB202190, the specific JNK inhibitor SP600125 and the specific ERK Inhibitor II. Furthermore, binding of AML-expressed GITRL to GITR on NK cells downregulates cellular cytotoxicity and IFN-γ production in AML-NK cell cocultures, which can be overcome by addition of GITR-blocking antibodies as determined by cytotoxicity assays and ELISA. Thus, our data indicate that GITRL expression in AML substantially influences tumor immunoediting and enables the escape of leukemia cells from NK cell-mediated immunosurveillance.

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Reducing TNF Receptor 2+ Regulatory T Cells via the Combined Action of Azacitidine and the HDAC Inhibitor, Panobinostat for Clinical Benefit in Acute Myeloid Leukemia Patients

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-13-1576 ◽

2013 ◽

Vol 20 (3) ◽

pp. 724-735 ◽

Cited By ~ 41

Author(s):

Chindu Govindaraj ◽

Peter Tan ◽

Patricia Walker ◽

Andrew Wei ◽

Andrew Spencer ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Regulatory T Cells ◽

Clinical Benefit ◽

Hdac Inhibitor ◽

Myeloid Leukemia ◽

Tnf Receptor ◽

Combined Action ◽

Acute Myeloid

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Depletion of Regulatory T Cells Dramatically Improves DC-Based Immunization Against Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v108.11.3694.3694 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3694-3694 ◽

Cited By ~ 1

Author(s):

Stephanie Delluc ◽

Auguste Gaston ◽

Carmen Marchiol-Fournigault ◽

Didier Fradelizi ◽

Armelle Regnault ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Acute Myeloid Leukemia ◽

Cd4 T Cells ◽

Myeloid Leukemia ◽

Nk Cell ◽

Critical Role ◽

Dramatic Improvement ◽

Acute Myeloid

Abstract Dendritic cell (DC)-based vaccination is a promising approach to enhance anti-tumor immunity that could be considered for patients with high risk acute myeloid leukemia (AML). We have already shown in human that DC pulsed with eluted peptides (EP) from autologous AML blasts (DC/EP) are able to induce CD4+ and CD8+ anti-leukemic immune response in vitro (Delluc S, Haematologica, 2005). In order to optimize this vaccination strategy for AML patients we developed a pre-clinical murine model. C57/Bl6 mice were vaccinated by DC pulsed or not with peptides eluted from the syngenic C1498 myelomonocytic leukemic cell line in a prophylactic setting. Injection of DC/EP induced an anti-leukemic response as shown by the cytotoxic activity of CD4 T cells, whereas the injection of unpulsed DC induced a NK cell-mediated cytotoxicity against C1498 cells. In vivo depletion of CD4 T cells or NK cells abrogated the protective effect induced by DC/EP (p=0.02) or DC (p=0.06) vaccination, respectively, confirming their critical role in preventing leukemic outgrowth. However, late C1498 re-challenge showed that the anti-leukemic immune response was insufficient to protect DC/EP vaccinated mice from death, suggesting an ineffective or absent long-lived memory response. Since several populations of T cells have regulatory properties potentially inhibiting anti-tumor responses, we hypothesized that CD25+ cell-depletion in vivo could enhance the protection induced by vaccination. Indeed, we observed a dramatic improvement of the survival of mice treated by an anti-CD25 antibody before vaccination compared to mice vaccinated by DC/EP alone (p<0.01). More interestingly, CD25 depletion allowed the generation of long-lived immune responses since mice were protected from a late re-challenge by C1498 cells. Our results strongly suggest that depletion of regulatory CD25 T cells before DC-based vaccination should be considered for immunotherapy of weakly immunogenic tumors such as AML.

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Increased Regulatory T Cells in Peripheral Blood of Acute Myeloid Leukemia Patients Rely on Tumor Necrosis Factor (TNF)-α–TNF Receptor-2 Pathway

Frontiers in Immunology ◽

10.3389/fimmu.2018.01274 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 12

Author(s):

Min Wang ◽

Chen Zhang ◽

Tian Tian ◽

Teng Zhang ◽

Ruiqing Wang ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Tumor Necrosis Factor ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Tumor Necrosis ◽

Tnf Receptor ◽

Tnf Α ◽

Necrosis Factor ◽

Acute Myeloid

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Mutated regions of nucleophosmin 1 elicit both CD4+ and CD8+ T-cell responses in patients with acute myeloid leukemia

Blood ◽

10.1182/blood-2011-11-394395 ◽

2012 ◽

Vol 120 (6) ◽

pp. 1282-1289 ◽

Cited By ~ 71

Author(s):

Jochen Greiner ◽

Yoko Ono ◽

Susanne Hofmann ◽

Anita Schmitt ◽

Elmar Mehring ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

T Cell ◽

Immune Responses ◽

Cd4 T Cells ◽

Myeloid Leukemia ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Acute Myeloid

Abstract Mutations in the nucleophosmin gene (NPM1mut) are one of the most frequent molecular alterations in acute myeloid leukemia (AML), and immune responses may contribute to the favorable prognosis of AML patients with NPM1mut. In the present study, we were able to demonstrate both CD4+ and CD8+ T-cell responses against NPM1mut. Ten peptides derived from wild-type NPM1 and NPM1mut were subjected to ELISPOT analysis in 33 healthy volunteers and 27 AML patients. Tetramer assays against the most interesting epitopes were performed and Cr51-release assays were used to show the cytotoxicity of peptide-specific T cells. Moreover, HLA-DR–binding epitopes were used to test the role of CD4+ T cells in NPM1 immunogenicity. Two epitopes (epitopes #1 and #3) derived from NPM1mut induced CD8+ T-cell responses. A total of 33% of the NPM1mut AML patients showed immune responses against epitope #1 and 44% against epitope #3. Specific lysis of leukemic blasts was detected. To obtain robust immune responses against tumor cells, the activation of CD4+ T cells is crucial. Therefore, overlapping (OL) peptides were analyzed in ELISPOT assays and OL8 was able to activate both CD8+ and CD4+ T cells. The results of the present study show that NPM1mut induces specific T-cell responses of CD4+ and CD8+ T cells and therefore is a promising target for specific immunotherapies in AML.

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