# THE T-CELL RECEPTOR'S ROLE IN T-CELL LYMPHOMA PATHOGENESIS

> **NIH NIH R37** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $317,232

## Abstract

Project Abstract
The majority of patients afflicted with a T-cell lymphoma (TCL) will experience disease progression and
ultimately succumb to their disease, as current therapies are rarely curative, and the underlying mechanisms
driving TCL progression and chemotherapy resistance are poorly understood. We have demonstrated that
antigen-presenting cells, particularly lymphoma-associated macrophages (LAM) are abundant constituents of
the tumor microenvironment (TME) in TCL, and directly promote the growth and survival of primary TCL cells
ex vivo. Blockade of the major histocompatibility complex (MHC), required for antigen presentation and T-cell
activation, inhibits LAM-induced proliferation of malignant T cells. Conversely, direct stimulation of the T-cell
receptor (TCR) on primary TCL cells culminates in the activation and upregulation of transcription factors that
promote the growth and survival of conventional T cells, including the zinc-finger transcription factor GATA-3.
We have recently shown that GATA-3 identifies a molecularly and clinically distinct subset of TCL that are
highly resistant to chemotherapy. Genetic and pharmacologic loss-of-function (and gain-of-function) strategies
further demonstrated that GATA-3 confers resistance to chemotherapy. Collectively, our preliminary data are
consistent with the hypothesis that TCR signaling and GATA-3-dependent gene expression are exploited by
malignant T cells and promote chemotherapy resistance. A paucity of TCL models amenable to genetic
manipulation and pharmacologic in vivo studies has hampered further progress. Therefore, the extent to which
antigenic stimulation and GATA-3-dependent gene expression promote T-cell lymphomagenesis and
chemotherapy resistance within the native tumor microenvironment, and within the context of a genetic
landscape resembling human TCL, remains uncertain. We have identified novel, and clinically achievable,
therapeutic strategies targeting the TCR, and we aim to extend those earlier findings here using primary TCL
cells and patient-derived xenografts (PDX). Our long-term goals are to understand the role of antigen-
presenting cells, and other constituents of the TME, in promoting T-cell lymphomagenesis; to identify the
lymphomagenic factors they provide, including those that are antigen, costimulatory, and cytokine receptor
dependent; and to develop novel therapeutic strategies exploiting these vulnerabilities that will improve
outcomes for patients afflicted with these NHL. Our overall objective here is to determine the mechanisms by
which the TCR and GATA-3 promote T-cell lymphomagenesis in vivo. This will be achieved by addressing our
central hypothesis that TCL progression, including resistance to chemotherapy, is regulated by TCR- and
GATA-3-dependent transcriptional programs. This hypothesis is well grounded in our own preliminary data,
and is entirely consistent with our current understanding of the genetic landscape and molecular pathogenesis
of the...

## Key facts

- **NIH application ID:** 10098010
- **Project number:** 5R37CA233476-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ryan A Wilcox
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $317,232
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098010

## Citation

> US National Institutes of Health, RePORTER application 10098010, THE T-CELL RECEPTOR'S ROLE IN T-CELL LYMPHOMA PATHOGENESIS (5R37CA233476-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10098010. Licensed CC0.

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