# Targeting CCL20-CCR6 Interactions in Colorectal Cancer

> **NIH VA I01** · VA BOSTON HEALTH CARE SYSTEM · 2020 · —

## Abstract

Nearly 1 in 20 people in the U.S. will be diagnosed with colorectal cancer in their lifetime, and over 1/3 of
these will die from the disease. In fact, colorectal cancer is the second leading cause of cancer-related
deaths in this country. Advances in prevention and treatment have made only a modest impact on
incidence and survival. Novel treatment strategies for colorectal cancer are clearly needed. Chemokines
have emerged as a crucial link between tumor-promoting inflammation and cancer. CCR6 is the only
known receptor for the inflammatory chemokine CCL20, which in turn is the only known ligand for CCR6.
Several lines of evidence suggest that interactions between the inflammatory chemokine CCL20 and its
receptor CCR6 play a key role in the development and progression of colorectal cancer. Correlative
evidence has suggested a possible role of CCR6 and CCL20 in promoting colorectal tumor growth,
invasion and metastasis. To date, however, beyond our preliminary results, there is a paucity of in vivo
data on the effect of disrupting CCL20-CCR6 interactions in colorectal cancer in the setting of an intact
immune system. We have demonstrated that both CCL20 and CCR6 are upregulated in human colon
cancers. We have found that deficiency of CCR6 is associated with a dramatic decrease in adenoma
formation in a model of spontaneous intestinal carcinogenesis and a marked decrease in tumor growth in a
syngeneic transplantable tumor model. We have observed that CCL20 signaling through CCR6 induces
further secretion of CCL20, and this in turn promotes proliferation and migration in colorectal cancer cells.
In addition to the epithelial cell effects of CCL20-CCR6 interactions, a stromal effect is evidenced by the
fact that in the tumor challenge experiments, the transplanted colon cancer cells expressed CCR6 in both
arms, yet growth was delayed in CCR6-deficient host mice. We have found that CCR6 deficiency is
associated with decreased macrophage migration into adenomas and transplanted colon cancers. We
have further demonstrated that CCL20-CCR6 interactions indeed induce monocyte/macrophage migration
in vitro and in vivo. Furthermore, we have observed that growth of transplanted colon cancer tumors is
delayed by depletion of tumor macrophages. Lastly, we have found that tumor macrophages secrete
inflammatory mediators, which in turn induce proliferation of colon cancer cells. In aggregate our
preliminary results imply that CCL20-CCR6 signaling promotes colorectal cancer through a direct effect on
neoplastic cancer cells as well as through effects on tumor stromal cells such as macrophages. We have
recently begun to test a novel, orally-available small molecule CCR6 inhibitor. Our preliminary data show
that this molecule can inhibit the CCL20 auto feedback loop, colorectal cancer cell proliferation, and
monocyte migration in vitro. Thus we hypothesize that targeting interactions between CCL20 and CCR6 is
effective for the treatment of colorectal cancer. To tes...

## Key facts

- **NIH application ID:** 9859316
- **Project number:** 5I01BX003771-03
- **Recipient organization:** VA BOSTON HEALTH CARE SYSTEM
- **Principal Investigator:** Jason Samuel Gold
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859316

## Citation

> US National Institutes of Health, RePORTER application 9859316, Targeting CCL20-CCR6 Interactions in Colorectal Cancer (5I01BX003771-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9859316. Licensed CC0.

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