Wnt/β-catenin regulates alloreactive T cells for the treatment of hematological malignancies

Mammadli, Mahinbanu; Harris, Robert G.; Mahmudlu, Sara; Verma, Anjali; A, May; R, Dhawan; At, Waickman; Jm, Sen; Karimi, Mobin

doi:10.1101/2021.04.12.439538

Cited by 3 publications

(1 citation statement)

References 59 publications

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“…2B-C). Considering that Eomes and T-bet have been reported to play a central role in anti-tumor responses, we hypothesized that by upregulating Eomes and T-bet, CD8 T cells lacking TCF-7 can maintain cytotoxicity, and that TCF-7 is not required for CD8 T cell-mediated cytolytic function [59]. We anticipated that CD8 T cells from TCF-7 cKO mice may have attenuated TCR signaling, so we examined this and other activating receptors by ow cytometry.…”

Section: Resultsmentioning

confidence: 99%

TCF-1 Regulates NKG2D Expression on CD8 T Cells During Anti-Tumor Responses

et al. 2022

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Section: Resultsmentioning

confidence: 99%

TCF-1 Regulates NKG2D Expression on CD8 T Cells During Anti-Tumor Responses

et al. 2022

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TCF-7is dispensable for anti-tumor response but required for persistent function of mature CD8 T cells

Harris

Mammadli

A³

et al. 2021

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for hematological malignancy due to graft-versus-leukemia (GVL) effects, mediated by alloreactive donor T cells. However, these same donor cells cause graft-versus-host disease (GVHD), a life-threatening complication. During GVHD, donor T cells proliferate, migrate, and produce cytokines, leading to damage of healthy host tissues. Separating the linked processes of GVHD and GVL is critical to improving outcomes. Here we show that TCF-1, a major T cell developmental factor, plays a role in regulation of these processes. Using a mouse model of allo-HSCT leading to GVHD, we found that conditional loss of TCF-1 in mature CD8 T cells separates GVHD from GVL, providing an optimal clinical phenotype. This occurred due to changes in cytokine production, proliferation, cell survival, chemokine receptor expression, and gene expression. Thus, modulation of TCF-1 signaling reduces GVHD severity and persistence, but maintains GVL effects, and could be useful for allo-HSCT or other T cell-mediated disorders. Furthermore, here and in our companion manuscript we show that regulation of mature, alloactivated T cells by TCF-1 differs between CD4 and CD8 T cells, suggesting that TCF-1 is critical for regulation of mature alloactivated T cells, with unique programs in each subset.

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TCF-1 regulates NKG2D expression on CD8 T cells during anti-tumor responses

Harris

Mammadli

Hiner

et al. 2022

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Cancer immunotherapy relies on improving T cell effector functions against malignancies, but despite the identification of several key transcription factors (TFs), the biological functions of these TFs are not entirely understood. We developed and utilized a novel, clinically relevant murine model to dissect the functional properties of crucial T cell transcription factors during antitumor responses. Our data showed that TCF-1 suppresses surface NKG2D expression on naïve and activated CD8 T cells via key transcriptional factors Eomes and T-bet.Using both in vitro and in vivo models, we uncovered how TCF-1 regulatescritical molecules responsible for peripheral CD8 T cell effector functions. Finally, our unique genetic and molecular approaches proved that TCF-1 also differentially regulates essential kinases. These kinases, including LCK, LAT, ITK, PLC-g1, P65, ERKI/II, and JAK/STATs, are required for peripheral CD8 T cell persistent function during alloimmunity. Overall, our molecular and bioinformatics data demonstrate the mechanism by which TCF-1 modulatedseveral critical aspects of T cell function during CD8 T cell response to cancer.

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Wnt/β-catenin regulates alloreactive T cells for the treatment of hematological malignancies

Cited by 3 publications

References 59 publications

TCF-1 Regulates NKG2D Expression on CD8 T Cells During Anti-Tumor Responses

TCF-1 Regulates NKG2D Expression on CD8 T Cells During Anti-Tumor Responses

TCF-7is dispensable for anti-tumor response but required for persistent function of mature CD8 T cells

TCF-1 regulates NKG2D expression on CD8 T cells during anti-tumor responses

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