# Augmenting T cell activity to weak tumor antigens and reversing myeloid cell-mediated T cell inhibition

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $366,484

## Abstract

Our long term goal is to develop a novel approach for treating established melanoma tumors by enhancing
cytotoxic T cell responses towards weakly immunogenic and lowly expressed tumor antigens (TAgs) including
neoantigens while simultaneously conferring T cells resistance to myeloid-derived suppressor cell (MDSC)–
mediated suppression. In clinical trials, T cell-based immunotherapies have demonstrated tumor regression
and increased survival rates. Yet despite these encouraging clinical results, durable antitumor responses are
observed in only a subset of patients with advanced melanoma. This discrepancy stresses the need for more
effective treatment strategies. T cell-based therapies are hindered in part by low T cell receptor (TCR) affinity
and/or avidity and by the low expression of TAg on the tumor cell's surface. Additionally, the presence of
MDSCs poses a major obstacle to generating effective and long-lived antitumor T cell responses. In our
published and preliminary studies, activating MyD88 signaling in T cells, via toll like receptor engagement,
augmented T cell responses and prolonged T cell survival. By fusing the CD8α (extracellular) to MyD88
(intracellular; CD8α:MyD88) molecule or by linking melanoma-reactive TCRs to MyD88 (TCR:MyD88) we have
developed a novel platform that strongly activates MyD88 signaling in a TLR-independent, strictly TCR-
dependent fashion. CD8α:MyD88 expression in T cells considerably amplifies responses to weak and
suboptimal levels of TAg and in a TCR-dependent manner, and in preliminary studies has demonstrated the
extraordinary property of differentiating MDSC's into cells that can enhance T cell responses. Importantly, the
use of CD8α offers the unique feature in that it represents a `universal' approach to potentiating T cell
responses, regardless of the patient's HLA type. Our central hypothesis is that T cells engineered to
express a CD8α:MyD88 (or TCR:MyD88) will amplify TCR signals against a variety of weakly
immunogenic or lowly expressed TAgs including neoantigens and reverse the suppressive activity of
myeloid cell suppression, resulting in effective and long-lived antitumor responses. Aim 1 is to
determine the molecular mechanisms by which MyD88 activation in T cells augments TCR signals. Through in
vitro studies of human and mouse cells, we will define the molecular interactions through which MyD88
signaling augments TCR responses to tumor antigens of varying affinities. Aim 2 is determine the fate and
antitumor efficacy of each CD8α:MyD88 and TCR:MyD88 T cells in mice with an established subcutaneous or
intracranial melanoma tumor. Aim 3 is to ascertain the in vivo significance and define the mechanism(s)
through which MyD88 signaling in T cells reverses myeloid cell's suppressive function. These studies are
clinically significant as they have the potential to offer mechanistic insights as to how TCR responses can be
amplified and, novel strategies for inhibiting and/or reversing MDSC function.

## Key facts

- **NIH application ID:** 9669010
- **Project number:** 5R01CA207913-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Eduardo V Davila
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,484
- **Award type:** 5
- **Project period:** 2018-12-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9669010

## Citation

> US National Institutes of Health, RePORTER application 9669010, Augmenting T cell activity to weak tumor antigens and reversing myeloid cell-mediated T cell inhibition (5R01CA207913-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9669010. Licensed CC0.

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