# IL-17-driven mechanisms for tumor progression and resistance to therapies

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $520,309

## Abstract

Project Summary
While the relationship between chronic inflammation and cancer is well recognized, knowledge of the cellular
and molecular mechanisms that link these processes continues to evolve. Intratumoral interleukin 17A (IL-17)
levels are associated with poor prognosis for a variety of solid tumors in human. The overall goal of this
application is to investigate the mechanisms of IL-17-mediated cancer progression, focusing on tumor responses
to anti-cancer therapies. Our recent preliminary data revealed that IL-17 engages both cancer cells and tumor
microenvironment to synergistically promote cancer progression. Firstly, work supported by this award identified
a non-canonical IL-17-induced EGFR-mediated ERK5 signaling cascade critical for tumorigenesis. Our new
preliminary study revealed an Lrig1+ stem-like tumor cell population in squamous cell carcinoma that are highly
responsive to IL-17 with EGFR-ERK5 activation. Transcriptomic profiling revealed a link between IL-17-ERK5
axis in human and mouse Lrig1+ stem-like tumor cells with NRF2-mediated antioxidation and Wnt5a-dependent
induction of stemness. Lineage tracing showed that IL-17 rendered these Lrig1+ stem-like tumor cells resistance
to chemotherapy, which were also enriched by anti-PD1 treatment. Secondly, we found that canonical IL-17
signaling operates in both tumor cells and stromal cells to dictate a tumor-promoting and immune suppressive
environment. In tumor cells, IL-17 synergizes with other inflammatory cytokines to orchestrate an intratumoral
cancer promoting inflammation via the induction of specific effector molecules. In cancer-associated fibroblasts,
IL-17 signaling helps to establish an immune exclusion zone to prevent the infiltration of CD8+ T cells. Deletion
of IL-17R in CAFs rendered these tumors sensitive to immune therapy. Based on these observations, we
hypothesize that canonical and non-canonical IL-17 signaling in cancer cells and CAFs coordinately drive cancer
progression and resistance to therapies. To test this hypothesis, we will (1) Investigate how IL-17R-EGFR axis
in Lrig1+ stem-like tumor cells renders resistance to anti-cancer therapies; (2) Elucidate the mechanism by which
IL-17 shapes the pro-tumor immune exclusive tumor microenvironment. Program Interactions: This Project will
be critically informed by and also provide necessary information to the other Projects in the Program at multiple
levels. Project 1 and Project 2 will investigate the antagonistic interplay between IFNβ and TGFβ in cancer cell
differentiation. Informed by those studies, we will determine whether STING-induced IFNβ can be used to
eradicate Lrig1+ cells to improve responses to anti-cancer therapies. We will take advantage of the Animal
Model, Immunotyping and Analytics Core B to standardize our in vivo analyses, including preclinical
assessment of cancer therapeutics and characterization of the tumor microenvironment (TME). Statistical
analyses will be performed by Program Biosta...

## Key facts

- **NIH application ID:** 10493940
- **Project number:** 1P01CA272161-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Xiaoxia Li
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $520,309
- **Award type:** 1
- **Project period:** 2022-09-13 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10493940

## Citation

> US National Institutes of Health, RePORTER application 10493940, IL-17-driven mechanisms for tumor progression and resistance to therapies (1P01CA272161-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10493940. Licensed CC0.

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