# Role for TbetaRIII Shedding in the Tumor Microenvironment

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $338,901

## Abstract

Transforming growth factor-β (TGF-β) superfamily ligands function to suppress then promote cancer
progression through mechanisms that remain to be fully defined. We have demonstrated that loss of type III
TGF-β receptor (TβRIII) expression is a frequent event in human cancers. TβRIII suppresses cancer
progression, in part, through ectodomain shedding that generates a soluble TβRIII (sTβRIII), which has the
potential to regulate signaling throughout the tumor microenvironment (TME). While restoring TβRIII
expression in cancer cells and/or sTβRIII treatment created an immunotolerant TME, the mechanisms and
relative contribution of TβRIII and sTβRIII in regulating the TME, as well as their respective roles in cancer
initiation and cancer progression have not been established. Here we defined the structural determinants
operant in regulating TβRIII shedding, which enabled us to create: i) a TβRIII super-shedder (TβRIII-SS) and ii)
a TβRIII non-shedder (TβRIII∆shed), with corresponding murine models. We have demonstrated that
neutrophils may regulate TβRIII shedding. Based on these results, we hypothesize that neutrophil-mediated
TβRIII loss/shedding/degradation in breast cancer and melanoma increases TGF-β superfamily signaling in the
TME via loss of sTβRIII in the TME, promoting cancer progression, in part, by creating an immunotolerant
TME. We further hypothesize that expressing sTβRIII or functional analogues to suppress TGF-β signaling in
the TME will circumvent a mechanism of resistance and increase the efficacy of current immunotherapy
approaches. We propose three Specific Aims. Aim 1: The mechanism by which neutrophils and the serine
proteases, cathepsin G (CTSG) and neutrophil elastase (ELANE), mediate TβRIII shedding/degradation in the
TME will be explored including defining structural determinants on TβRIII mediating shedding. Aim 2: We will
define whether loss of TβRIII/sTβRIII increases TGF-β superfamily signaling in the TME to create an
immunotolerant TME to promote cancer initiation or progression. Aim 3: We will define whether expressing
sTβRIII or functional analogues in the TME in conjunction with current immunotherapy approaches will result in
more effective therapies for breast cancer and melanoma and whether serum sTβRIII or TGF-β1 levels
function as predictive biomarkers. These studies will help define the biological functions of ectodomain
shedding of TβRIII in the context of the TME, providing broad impact on understanding the role of TGF-β
superfamily signaling in human cancer initiation and progression, while providing proof of principle for
combining anti-TGF-β signaling therapy with current immunotherapy approaches.

## Key facts

- **NIH application ID:** 10092129
- **Project number:** 5R01CA236843-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** GERARD C BLOBE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $338,901
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092129

## Citation

> US National Institutes of Health, RePORTER application 10092129, Role for TbetaRIII Shedding in the Tumor Microenvironment (5R01CA236843-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10092129. Licensed CC0.

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