# Type I Interferon Regulation of Tumor Cell and Immune Cell Interaction in Human Colon Cancer

> **NIH VA I01** · CHARLIE NORWOOD VA MEDICAL CENTER · 2023 · —

## Abstract

Project Summary
 IFN was an FDA-approved agent for human cancer therapy and is currently used as exogenous
recombinant protein or protein prodrugs. The use of IFN in human cancer therapy has been limited by the
ineffective dosing and high toxicity. This proposal develops a lipid nanoparticle encapsulated IFN-encoding
DNA nanoplasmid (IFNA13CO01) to force tumor cells to express and produce endogenous IFN13 locally in
the tumor microenvironment. IFNA13CO01 therapy is therefore expected to produce high level of endogenous
IFN13 locally in the tumor site and thus overcomes the ineffective dosing and systemic toxicity issues
associated with the current IFN agents. In the preliminary studies, we determined that type I interferon (IFN-I:
IFN and IFN) expression level is significantly lower in human colorectal carcinoma than in normal colon
tissue. We further determined that IFN-I functions in both tumor cells and T cells are essential for host cancer
immune surveillance. Mechanistically, we determined that IFN-I activates STAT3 that binds to the Gzmb
promoter to activate Gzmb transcription in CTLs. The IFN-I/STAT3/Gzmb axis thus is essential for CTL anti-
tumor function. In addition, we determined that tumor cell expressed PD-L1 (tPD-L1) engages myeloid cell
expressed PD-1 (mPD-1) to antagonize IFN-I and STAT1 signaling to repress Cxcl9 and Cxcl10 to impair CTL
recruitment to lung metastases. Human patient response to PD-1 blockade immunotherapy correlates with
IFN-I response in myeloid cells. We therefore discovered that the tPD-L1/mPD-1/IFN-I/STAT1/Cxcl9-Cxcl10
axis controls CTL tumor infiltration in lung metastasis. Our central hypothesis is that forcing tumor cells to
express and produce endogenous IFN13 in the local tumor microenvironment via IFNA13CO01 therapy is an
effective and yet safe approach to suppress human colorectal tumor growth and progression. We propose to
test our new central hypothesis by pursuing the following 3 specific aims: 1) Test the hypothesis that tPD-1
engages mPD-1 to inhibit IFI-I signaling to suppress CTL recruitment and function to promote metastatic tumor
growth in human colon cancer patients.; 2) Determine the efficacy of IFNA13CO01 in suppression of
metastatic human colon cancer PDX growth in humanized NSG mice; and 3) Determine IFNA13CO01
biodistribution, toxicology and pharmacokinetics in vivo.

## Key facts

- **NIH application ID:** 10590049
- **Project number:** 2I01CX001364-05
- **Recipient organization:** CHARLIE NORWOOD VA MEDICAL CENTER
- **Principal Investigator:** KEBIN LIU
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2019-01-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10590049

## Citation

> US National Institutes of Health, RePORTER application 10590049, Type I Interferon Regulation of Tumor Cell and Immune Cell Interaction in Human Colon Cancer (2I01CX001364-05). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10590049. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*