# Functional reprogramming of tumor-MDSC through antibody-based therapies targeting Notch ligands

> **NIH NIH R01** · H. LEE MOFFITT CANCER CTR & RES INST · 2021 · $393,450

## Abstract

Abstract
The accumulation of Myeloid-derived suppressor cells (MDSC) in individuals with cancer has emerged as a
major mechanism of evasion of anti-tumor immunity and a primary obstacle to the development of efficient
cancer immunotherapies. Despite their undeniable relevance in tumor-induced immune suppression, there are
no current approaches to effectively block the immunosuppressive activity of MDSC in patients with cancer.
Thus, novel therapeutic strategies to inhibit MDSC are urgently needed. Throughout the proposed research,
we aim to determine the mechanisms by which the antibody-based blockade of the Notch ligands Jagged1-2 in
tumor-bearing hosts functionally transforms MDSC into myeloid subsets that prime anti-tumor T cell responses.
This is supported by crucial supporting results showing that treatment of tumor-bearing hosts with a humanized
blocking antibody that recognizes the human and murine Jagged1-2 (CTX014) significantly delayed tumor
growth and transformed MDSC into cellular populations that promoted the infiltration of reactive CD8+ T cells
into tumors and enhanced the efficacy of T cell-based immunotherapy. Therefore, we hypothesize that: 1) The
expression of Jagged1-2 in cancer cells and/or tumor-infiltrating MDSC plays a central role in the suppression
of protective T cell immunity in tumors; and 2) Treatment of tumor-bearing mice with anti-Jagged1-2 therapy
functionally reprograms MDSC, overcomes tumor-related T cell suppression, and increases the efficacy of
promising cancer immunotherapies. To test these postulates, we proposed the following Specific Aims: 1)
Determine the role of cancer cell-Jagged1-2 in the immunosuppressive activity induced by MDSC in tumor-
bearing hosts; 2) Elucidate the mechanisms leading to the upregulation of Jagged ligands in tumor-MDSC and
understand the endogenous effects of MDSC-expressed Jagged1 in tumor-induced tolerance; 3) Test the
prediction that the combined inhibition of Jagged in cancer cells and MDSC overcomes tumor-induced T cell
suppression and enhances the efficacy of various forms of immunotherapy. Completion of this highly
innovative and translational research will elucidate the role of Jagged1 and 2 as primary mediators for the T
cell dysfunction occurring in tumors and pave the way for the development of a novel therapeutic approach to
functionally reprogram MDSC in patients with cancer, which is expected to prevent and/or reverse tumor-
induced T cell tolerance and boost the efficacy of promising forms of cancer immunotherapy.

## Key facts

- **NIH application ID:** 10169379
- **Project number:** 5R01CA233512-03
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Paulo Cesar Rodriguez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,450
- **Award type:** 5
- **Project period:** 2019-06-06 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169379

## Citation

> US National Institutes of Health, RePORTER application 10169379, Functional reprogramming of tumor-MDSC through antibody-based therapies targeting Notch ligands (5R01CA233512-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10169379. Licensed CC0.

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