# Role of the tumor NLRP3 inflammasome in the generation of anti-PD-1 antibody immunotherapy-associated toxicities

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $396,432

## Abstract

The recent success and expanded use of the checkpoint inhibitor immunotherapies in clinical oncology
has resulted in an increased incidence of a variety of immune-related adverse events (irAEs), some of
which can have a lasting impact on the lives of our patients. The continued development of adjuvant
immunotherapy protocols and more potent immunotherapy combinations such as the
ipilimumab/nivolumab regimen is expected to increase the incidence and societal impact of these irAEs.
Despite their growing prevalence, the underlying pathogenesis of individual irAEs is poorly understood
and our therapeutic management of these conditions remains crude.
 Using a genetically engineered model of melanoma, we have found that anti-PD-1 antibody (ab)
immunotherapy routinely leads to neutrophilic infiltration of the lung parenchyma and colon lamina
propria, closely resembling the pathology noted in human checkpoint inhibitor-associated pneumonitis
and colitis, respectively. This work further revealed that anti-PD-1 ab treatment of non-tumor-bearing
mice eliminates the development of these irAEs, suggesting the presence of a tumor-intrinsic pro-
inflammatory mechanism. As part of this work, we have recently identified a tumor-intrinsic PD-
L1:NLRP3:HSP70 signaling axis that drives the accumulation of neutrophils in distant organs including
the lungs and colon in response to PD-1 blockade. Additional studies have shown that genetic knock-
out of tumor HSP70 expression and the pharmacological inhibition of the NLRP3 inflammasome
suppresses the accumulation of neutrophils in these distant tissues. Based on these findings, we now
hypothesize that the tumor NLRP3 inflammasome promotes the development of checkpoint inhibitor-
associated colitis and pneumonitis and that NLRP3 represents a promising pharmacological target for
suppressing the development of these irAEs. To address this hypothesis, we have generated a
transgenic melanoma tissue-specific NLRP3-/- model to examine the role of tumor-intrinsic NLRP3 in
the development of checkpoint inhibitor-induced colitis and pneumonitis. Additional studies will address
a potential role for this tumor NLRP3 pathway in Th17 differentiation in these distant organ tissues and
whether a small molecule inhibitor of NLRP3 would be a superior option over steroids for the
management of colitis and pneumonitis in an autochthonous melanoma model undergoing anti-PD-1
ab immunotherapy. We will further utilize tumor tissue and DNA collected from patients undergoing
checkpoint inhibitor immunotherapy on an active IRB-approved clinical study to determine if genetic
variations of NLRP3 may contribute to the development of these irAEs. Overall, this work will provide
unique mechanistic insight into the development of irAEs and identify rational therapeutic strategies
and predictive biomarkers for improving the management of patients undergoing immunotherapy.

## Key facts

- **NIH application ID:** 10263391
- **Project number:** 1R01CA251136-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Brent Allen Hanks
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,432
- **Award type:** 1
- **Project period:** 2021-07-20 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10263391

## Citation

> US National Institutes of Health, RePORTER application 10263391, Role of the tumor NLRP3 inflammasome in the generation of anti-PD-1 antibody immunotherapy-associated toxicities (1R01CA251136-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10263391. Licensed CC0.

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