# Deciphering the immunogenicity of cell death using systematic genetic tools

> **NIH NIH DP2** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $492,000

## Abstract

Project Summary
Professional phagocytes, including macrophages and dendritic cells, engulf approximately 200 billion dead cells
per day in humans. The vast majority of dead cells are consumed “silently,” in that the phagocyte does not trigger
an adaptive immune response targeting the material in the engulfed cell, thereby maintaining tolerance of self.
Phagocytes play a critical role in maintaining self-tolerance, and their accurate decision-making during
phagocytosis is essential for avoiding catastrophic immune rejection of self antigens. On the other hand,
immunogenic cell death (ICD), in which an engulfed cell is interpreted as having died following infection with a
pathogen, is critical for launching an effective immune response against viral pathogens and tumors. The
immunogenicity of pathogen-induced cell death is known to depend on the detection of pathogen-associated
molecular patterns (PAMPs) by pattern recognition receptors (PRR) in phagocytes. By contrast, the mechanisms
governing the regulation of ICD in sterile contexts (such as autoimmunity and cancer) are significantly less well
understood. Our lack of knowledge of the molecular signals that govern ICD directly impedes our ability to
develop rational therapeutic strategies to either trigger or suppress ICD. We argue that the absence of systematic
genetic tools for understanding this complex, inter-cellular process has critically hindered the progression of the
ICD field. We propose a systematic approach for investigating the mechanisms governing ICD, building on our
recent development of a suite of platforms for high-throughput interrogation of the genetics of myeloid cell biology.
We will focus our efforts on three key “blind spots” in our knowledge of the three sequential stages of ICD: 1) the
mechanism of calreticulin-independent cellular uptake, 2) the mechanism of DAMP/adjuvant release by dead cells,
and 3) the mechanisms governing PRR-driven antigen presentation in APCs. The project is designed to have high
impact by providing the first systematic investigations of this core immunological process and by potentiating
therapeutic targeting of these pathways in autoimmunity, cancer, and infectious diseases.

## Key facts

- **NIH application ID:** 10951271
- **Project number:** 1DP2AI184830-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Roarke Alexander Kamber
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $492,000
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10951271

## Citation

> US National Institutes of Health, RePORTER application 10951271, Deciphering the immunogenicity of cell death using systematic genetic tools (1DP2AI184830-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10951271. Licensed CC0.

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