# The role of Interleukin 17RB signaling in colorectal cancer progression

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2022 · $471,181

## Abstract

Despite important advances in detection, surgery and chemotherapy, colorectal cancer (CRC) is the second
cause of cancer death in the U.S. Most of these deaths are due to cancer progression and the subsequent
development of metastatic disease and therapy resistance. New targets, ideally targets whose inhibition could
suppress tumor growth, metastasis and therapy resistance, are still sorely needed. Accumulating data on usage
of non-steroidal anti-inflammatory drugs reveals that inhibition of inflammation remarkably lowers the risk of
cancer death, especially in CRC, indicating that inflammation may be a critical driver of cancer progression and
metastasis beyond rare cases of colitis-associated cancer. We postulated that many apparently “non-
inflammatory” solid tumors have a surprising ability to recruit immune cells and upregulate inflammatory
mediators- a phenomenon named “tumor-elicited inflammation” (TEI). However, the exact molecular and cellular
mechanisms of how inflammation regulates cancer progression, metastasis and therapy resistance are not fully
understood, delaying identification and validation of new targets in cancer.
In our preliminary studies, we specifically identified the IL-17B, and its receptor IL-17RB, pathway as: 1)
upregulated in inflammation, CAC and CRC; 2) correlated with poor prognosis in human patients, and with
expression of immune checkpoints that are required for inhibition of specific anti-tumor immune responses; 3)
essential for CAC and CRC progression and inflammation 4) a molecular pathway whose inactivation reduced
CAC and CRC, while other known inflammatory mediators are still present 5) a pathway, which controls both
cancer cells and myeloid cell of microenvironment. This suggested that IL-17B/RB signaling is a key regulator
of TEI and CRC tumorigenesis. Here we will test this hypothesis by defining the contribution of IL-17B/RB
signaling to CRC progression, metastasis and response to therapy, and evaluting its mechanism of action,
using multi-allele composite genetic murine models that mimic human CAC and CRC disease. As IL-17RB is
expressed by both epithelial (cancer) cells and myeloid cells, we developed novel, conditional models of IL-
17RB deficiency in each cell type to allow us to dissect the cell-type-specific roles of IL-17RB signaling in TEI.
Specific Aims for this project are the following: (1) Define the contribution for IL-17RB signaling and its
mechanism action in CRC tumorigenesis. (2) Delineate the role of IL-17RB in CRC progression and
metastasis. (3). Evaluate therapeutic targeting of IL-17RB to curb inflammation and CRC tumorigenesis.
Overall these studies will establish a rationale for the specific inhibition of inflammation by targeting the IL-
17RB pathway as a strategy to halt CRC growth, progression and metastasis. Our long-term goal is to better
understand the components of the inflammatory milieu in CRC progression, and thus define molecular
predictors of primary and recurrent met...

## Key facts

- **NIH application ID:** 10180913
- **Project number:** 5R01CA227629-05
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Sergei I Grivennikov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $471,181
- **Award type:** 5
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180913

## Citation

> US National Institutes of Health, RePORTER application 10180913, The role of Interleukin 17RB signaling in colorectal cancer progression (5R01CA227629-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10180913. Licensed CC0.

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