# Defining immune footprint in tumor microenvironment following high salt synergized inflammatory cytokine mediated breast cancer progression

> **NIH NIH U54** · MEHARRY MEDICAL COLLEGE · 2020 · $75,660

## Abstract

Summary
Chronic inflammatory milieu and compromised T-cell immune-surveillance in the tumor microenvironment is
suggested to play a decisive role in cancer progression and metastasis. Although various immune effector
cells are recruited to the tumor site, their anti-tumor function is down-regulated in response to signals derived
from the tumor microenvironment. However, the precise molecular signals for this mechanism remain poorly
characterized. Our preliminary studies have demonstrated that stimulation of naive human CD4+T cells and
monocytes with high NaCl concentrations (0.2 M) resulted in a temporal-dependent bimodal effect on IL-17
secretion, with an initial increase (1-3 days), followed by a decrease in IL-17 secretion (5-7 days), and an
increase in anti- inflammatory IL-10 secretion. This later phase decrease in IL-17 after exposure to high salt
is accompanied by enhanced activation of immune-suppressive Tregs(CD4+Foxp3+) and MΦ2-like
macrophages, along with up-regulation of immune exhaustion markers (CTLA4, PD1, Tim3, LAG3) in CD4+T
cells. Thus, we hypothesize that high-salt concentration in the tumor microenvironment is linked to
modulation of IL-17, resulting in tumor growth with immune-exhaustion and immune-suppression responses.
These events lead to a dysfunctional late phase effector immune-elimination, culminating to enhance cancer
progression and metastasis. Using murine breast cancer models where mice are fed a diet with varying salt
content, we will utilize advanced sodium(Na23)-MRI and immunological techniques to test this hypothesis
with the following two specific aims: (1) Define and characterize the temporal effect on the functional changes
in infiltrating Treg (CD4+FoxP3+IL-10+T cells), Th17(CD4+IL-17+T cells), and macrophages (MΦ1/MΦ2
switch) leading to breast cancer progression; (2) Define the role of immune check-point inhibitors, CTLA4
and PD1 mAb, in high salt-mediated tumor progression compared to checkpoint inhibitor therapy combined
with a low-salt diet in two mouse models of breast cancer. We envision that the outcomes of this study will
help delineate the molecular mechanisms involved in high salt-mediated dysfunction of immune responses in
the tumor microenvironment with a potential clinical translational relevance of lowering salt tissue levels in
patients undergoing treatment with immune-check point inhibitors.
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## Key facts

- **NIH application ID:** 10012769
- **Project number:** 5U54CA163069-10
- **Recipient organization:** MEHARRY MEDICAL COLLEGE
- **Principal Investigator:** Anil Shanker
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $75,660
- **Award type:** 5
- **Project period:** 2011-09-26 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10012769

## Citation

> US National Institutes of Health, RePORTER application 10012769, Defining immune footprint in tumor microenvironment following high salt synergized inflammatory cytokine mediated breast cancer progression (5U54CA163069-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10012769. Licensed CC0.

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