# Mechanisms of durable antitumor immunity via CD26hiCD4+ T cells

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $368,628

## Abstract

PROJECT SUMMARY
Adoptive cell transfer (ACT) therapies for cancer patients have failed to fulfill their therapeutic promise, due to
the transfer of short-lived and terminally differentiated cells. A lack of means for developing durable T cell
potency has hampered ACT advancement in the clinic. Understanding and manipulating the pathways that
sustain T cell memory will potentially unlock durable responses to tumors. We recent found that IL-17A/IFN-
γ/IL-22-producing CD4+ T cells that express enzymatically active CD26 on their cell surface–termed human
CD26hiCD4+ T cells–demonstrate exquisite responses to tumors compared to Th1, Th2 or Th17 cells. Further
investigation revealed that these cells potently induce the expansion and engraftment of cytotoxic CD8+ T cells
in vivo. Interestingly, we found that abrogating the enzymatic activity of CD26 on CD26hiCD4+ but not on CD8+
or CD26negCD4+ T cells with Alogliptin impaired their capacity to secrete IFN-γ. Collectively, our data suggest
that CD26 plays a role in the cytotoxicity of CD26hiCD4+ T cells and could augment CD8+ T cell engraftment in
vivo, in turn mediated curative responses in mice with murine and human tumors. The importance of CD26 on
CD26hiCD4+ T cell function, metabolism and cytotoxicity will be investigated using various tools to
pharmaceutically or genetically manipulate CD26 enzyme activity. Based on our new findings, the loss of
function, metabolism and memory induced by the inhibition of CD26 enzymatic activity could potentially reduce
the ability of CD26hiCD4+ T cells to support CD8+ T cells. It is important to deduce how CD26 on CD26hiCD4+ T
cells cancer immunotherapy and if this activity and co-signaling molecules can be targeted for enhance therapy
against this aggressive pancreatic cancer. We propose to gain further insight into CD26hiCD4+ T cell-mediated
tumor immunity, hypothesizing that CD26 plays a crucial role in the anti-tumor activity of human CD26hiCD4+ T
cells as well as their ability to support CD8+ T cells (Aim 1), and that these cells have unique self-renewing
properties that prolong their efficacy of cancer immunotherapy after multiple rounds of serial transfer (Aim 2).
We will also target co-stimulatory molecules on these cells to enhance their capacity to kill human pancreatic
cancer (Aim 3). Our proposed research is expected to demonstrate that manipulation of the CD26 pathway
may induce durable immunity against the growth and recurrence of advanced malignancies.

## Key facts

- **NIH application ID:** 10227546
- **Project number:** 7R01CA208514-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Chrystal Mary Paulos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,628
- **Award type:** 7
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10227546

## Citation

> US National Institutes of Health, RePORTER application 10227546, Mechanisms of durable antitumor immunity via CD26hiCD4+ T cells (7R01CA208514-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10227546. Licensed CC0.

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