# Cytokine-mediated regulation of immunity and microenvironment in colorectal cancer metastasis

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2024 · $681,537

## Abstract

PROJECT SUMMARY/ABSTRACT
Colorectal cancer (CRC) is a second cause of cancer-related mortality because of metastatic disease
represented by liver and peritoneal metastasis. This disease is largely insensitive to modern immunotherapies
and is with limited curative options. Immune mechanisms regulating CRC tumor microenvironment (TME) are
not well understood and are likely to hold the key for better immune-based therapies.
 We surprisingly found that the levels of Interleukin (IL)27 cytokine are increased in human CRC and
relevant mouse models of CRC and that its increased levels correlate with poor prognosis. As a part of
preliminary data we found that genetic inactivation of IL27R (receptor) or neutralization of IL27 cytokine in
sporadic CRC models reduces tumor growth, progression and metastasis. This proposal aims to understand
how IL27 regulates CRC TME during metastasis development and how its inactivation drives anti-tumor immunity
exerted by innate and adaptive arms of immune responses.
 Our hypothesis is that IL27 suppressed anti-tumor immune responses mediated by adaptive immune T
cells and possible cells of innate immunity. We will use genetic models of IL27/IL27R deficiency as well as
neutralization of IL27 cytokine combined with cutting edge preclinical models of CRC spread and metastasis
and histological, cutting-edge imaging and molecular biological/advanced transcriptomics methods in mouse
and human CRC.
 Proposal will be based on three interconnected Specific Aims: 1) Examine effects of IL27 on
immunosuppressive TME of CRC liver and peritoneal metastasis; 2) Uncover cell type specificity of IL27 signals
within TME of CRC metastasis; 3) Test whether IL27 neutralization can aid other immunotherapeutic modalities,
particularly focuses on reactivation of adaptive (anti-PD1/anti-LAG3) and innate myeloid cell anti—cancer
immune responses (anti-CD47).
 Our experiments will therefore establish an unique role for IL27 signaling in liver and rarely studied
peritoneal CRC metastasis, uncover underlying molecular and cellular mechanisms and establish and test
rationale and feasibility of IL27 pathway blockade to facilitate anti-cancer immunity in difficult-to-treat advanced
cancer.

## Key facts

- **NIH application ID:** 10826683
- **Project number:** 1R01CA287786-01
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Sergei I Grivennikov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $681,537
- **Award type:** 1
- **Project period:** 2024-01-09 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10826683

## Citation

> US National Institutes of Health, RePORTER application 10826683, Cytokine-mediated regulation of immunity and microenvironment in colorectal cancer metastasis (1R01CA287786-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10826683. Licensed CC0.

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