# Autoinflammation in Human Melanoma

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2022 · —

## Abstract

PROJECT SUMMARY/ABSTRACT
Melanoma has a high propensity for metastasis and accounts for 80% of skin cancer-related deaths. Despite
the progress in melanoma therapeutics over the last several years, melanoma remains a challenge in clinical
oncology. The immune system plays an important role in controlling and eliminating cancer. However, tumors
often evade/escape immune attack by modifying their phenotypes and inducing immunosuppression. Recent
breakthrough in treating cancers with immune checkpoint inhibitors has fueled the intensive investigation of
new therapeutic targets, including negative regulators of adaptive and innate immune systems. We have
found that human metastatic melanoma cells spontaneously secrete biologically active interleukin (IL)-1β in
the absence of exogenous stimuli because of constitutive activation of IL-1 receptor signaling and a
multi-protein complex, “inflammasome”, exhibiting a feature of “autoinflammation” (IL-1β-mediated
dysregulation of immune system). IL-1β is a pleiotropic pro-inflammatory cytokine and plays a critical role in
tumor progression, immunosuppression and chemoresistance.
Peripheral blood is an information reservoir and represents systemic processes altered by the presence of
tumor cells. We conducted transcriptome profiling of whole blood cells from melanoma patients, and identified
differentially expressed genes in human melanoma blood. Of these, we identified a unique cytokine, IL-37,
which was highly upregulated in metastatic melanoma blood. IL-37 is a homolog of the IL-1 cytokine family.
Dinarello (co-I)’s group has found that IL-37 is a novel inhibitor of innate immunity. PI’s group has found that
IL-37 is a novel inhibitor of adaptive immunity. IL-37 is induced in pro-inflammatory milieu containing IL-1.
We hypothesize that IL-37 is induced by autoinflammation in human melanoma, leading to tumor-induced
immunoevasion. We propose to test this hypothesis using tumor and blood samples from melanoma patients
(in Aim 1) and unravel the immunoevasive mechanisms of action of IL-37 in tumor cells (in Aim 2) and blood
cells (in Aim 3) in melanoma. The specific aims are:
Aim 1: To identify cellular source of IL-37 expression in human melanoma samples and determine the link
between IL-37 and autoinflammation in human melanoma.
Aim 2: To define biological and mechanistic effects of IL-37 in melanoma cells.
Aim 3: To define biological and mechanistic effects of IL-37 in blood cells.
IL-37, an inhibitor of innate and adaptive immunity, has not been investigated in tumor immunity. Elucidating
the link between autoinflammation and immune escape, and understanding the role of IL-37 in tumor immune
escape is critical for clinical success in melanoma and will lead to the development of effective therapeutic
agents for cancer.

## Key facts

- **NIH application ID:** 10451489
- **Project number:** 5I01BX001228-09
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** Mayumi Fujita
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451489

## Citation

> US National Institutes of Health, RePORTER application 10451489, Autoinflammation in Human Melanoma (5I01BX001228-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10451489. Licensed CC0.

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