# Memory potential, molecular characterization, and translational applications of the novel ThEO/TcEO T cell phenotype

> **NIH NIH K00** · VANDERBILT UNIVERSITY · 2020 · $78,427

## Abstract

Melanoma is an aggressive form of skin cancer that accounts for the majority of skin cancer related deaths.
Newly developed therapeutic modalities, however, have offered hope in treating this once incurable disease.
Advances in immunotherapy, particularly the approval of anti-CTLA-4 and anti-PD-1 therapy for melanoma and
non-small-cell lung cancer have demonstrated the potential of immune modulation in not only treating, but
curing metastatic cancers. The clinical success of these checkpoint blockade antibodies has expanded the
potential of targeting other T cell co-receptor targets to potentiate robust anti-tumor immune responses that
may afford greater clinical benefit. Use of agonist antibodies directed towards 4-1BB, a co-stimulatory receptor
expressed on activated T cells, has proven effective in treating multiple tumor types in both murine systems
and early human clinical trials. The exquisite potency of α4-1BB therapy in boosting anti-tumor immunity is
due, in part, to 4-1BB-mediated programming of T cells to assume a highly cytotoxic phenotype driven by the T
box transcription factor Eomesodermin (Eomes) and characterized by expression of the co-inhibitory receptor
KLRG1. These Eomes+KLRG1+ CD8 (TcEO) and CD4 (ThEO) T cells mediate potent anti-tumor responses
capable of complete tumor rejection. We hypothesize that this Eomes-driven ThEO/TcEO T cell
phenotype represents a novel molecular program which forms stable immunologic memory despite
maintenance of highly cytotoxic effector function and KLRG1 expression. By characterizing the unique
pathways downstream of 4-1BB activation which create the ThEO program, we will establish the molecular
basis for the exquisite cytotoxicity of these cells, as well as their paradigm-breaking capacity to express
KLRG1 yet retain proliferative capacity and memory potential. Investigating the detailed memory phenotype of
these cells, as well as their replicative capacity and longevity following antigenic rechallenge will deepen our
understanding of 4-1BB agonist antibody immunobiology and provide insight into their translational value in a
cell therapy setting. Finally, exploring the importance of ThEO phenotype T cells for mediating both the
beneficial anti-tumor efficacy as well as the detrimental liver inflammation associated with 4-1BB agonist
antibody will provide mechanistic insights as well as potential guiding biomarkers for future clinical studies. The
proposed research project will provide extensive technical training in both basic and clinical research, scientific
writing, collaboration, and lab management necessary to pursue a career as an independent investigator.

## Key facts

- **NIH application ID:** 9908060
- **Project number:** 5K00CA212447-05
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Todd Bartkowiak
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $78,427
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908060

## Citation

> US National Institutes of Health, RePORTER application 9908060, Memory potential, molecular characterization, and translational applications of the novel ThEO/TcEO T cell phenotype (5K00CA212447-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9908060. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*