# To Elucidate the Biological Function and Translational Potential of NLRP3 in Immunotherapy-resistant Melanoma

> **NIH VA IK2** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2024 · —

## Abstract

Skin cancer is the most common form of cancer in the United States and melanoma accounts for
the vast majority of skin cancer deaths. Notably, Veterans have an increased risk of developing
and dying of melanoma compared to the general population. Albeit immunotherapy with immune
checkpoint inhibitors (ICI) has revolutionized the treatment of melanoma, significantly improving
the outcome of patients with this disease, the outcomes remain poor for Veterans with advanced
melanoma. Furthermore, only 40-60% of patients experience lasting medical benefits from ICL
The candidate's long-term goal is to develop new therapeutic strategies aimed at targeting this
subpopulation. The significant number of refractory and relapse cases, represents an important
unmet clinical need for the treatment of melanoma and proves that immune regulators such as
PD-1, PD-L 1 and CTLA-4 are not the only determinants of melanoma progression and immune
evasion. Notably, while inflammation has been demonstrated to influence melanoma growth and
response to checkpoints inhibitors, no therapy developed to date is designed to target it This is
because the tumor inflammatory pathway(s) that facilitates melanoma progression and reduces
the response to immunotherapy are still poorly characterized. For this reason, the candidate's
research has focused on melanoma-induced inflammation with the goal of identifying
opportunities for therapeutic intervention. The hypothesis of this study is that NOD-, LRR- and
pyrin domain containing 3 (NLRP3) activation reduces the efficacy of immunotherapy with
checkpoint inhibitor by inducing myeloid-derived suppressor cells (MDSCs) expansion, ultimately
suppressing the cos+ T and NK cells activity. The candidate further hypothesizes that NLRP3
inhibition can reverse the immunosuppressive tumor microenvironment, thereby resensitizing
immunotherapy-resistant melanomas to ICI therapy. Aim1 will elucidate whether NLRP3
regulates immunosuppressive mechanism(s), including PD-L 1 expression, in melanoma cells
reducing the response to ICL Aim2 will determine whether NLRP3 activation is employed by
melanoma cells to suppress the host immune system. The candidate will study this by
investigating the importance of NLRP3 activation on the paracrine activity of melanoma cells on
immune regulatory cells like MDSCs. Aim 3 will investigate whether inhibition of NLRP3 in
combination with anti-PD-1 in vivo increases the response and durability of immunotherapy using
a translationally relevant model. In conclusion, these studies will establish whether NLRP3 drives
resistance to ICI in melanoma, providing new insights into tumor biology, tumor immunology, and
cancer therapeutics.
Project Summary/Abstract

## Key facts

- **NIH application ID:** 10801525
- **Project number:** 1IK2BX006147-01A2
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** Carlo Marchetti
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801525

## Citation

> US National Institutes of Health, RePORTER application 10801525, To Elucidate the Biological Function and Translational Potential of NLRP3 in Immunotherapy-resistant Melanoma (1IK2BX006147-01A2). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10801525. Licensed CC0.

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