# Interrogating the Fgl2-FcgRIIB axis: A novel mechanism mediating apoptosis of tumor-specific memory CD8+ T cells

> **NIH NIH K00** · ALLEN INSTITUTE · 2024 · $90,715

## Abstract

PROJECT SUMMARY
One in fifty Americans will be diagnosed with melanoma in their lifetime and skin cutaneous melanoma is the
deadliest skin cancer. Cancer immunotherapy is a breakthrough approach to treat this disease and cytotoxic
CD8+ T-cell tumor infiltration is a critical factor to immunotherapeutic success. As such, identifying effective
strategies to increase the magnitude and functionality of the patient’s tumor-specific CD8+ T-cell response
remains an important goal. Inhibitory molecules on CD8+ T cells are imperative to T-cell signaling and immune
homeostasis. However, elevated expression of these molecules is correlated with dampened antitumor effector
response as well as poorer patient survival. FcγRIIB is an inhibitory Fc receptor recently discovered on a subset
of CD8+ T cells. FcγRIIB+ CD8+ T cells exhibit increased expression of activation markers, higher proliferative
ability, and secrete more proinflammatory cytokines than their FcγRIIB- counterparts in mice and humans,
making them imperative to the antitumor response. Recently, we discovered that an immunosuppressive
cytokine, fibrinogen-like protein 2 (Fgl2), is a ligand that binds FcγRIIB on CD8+ T cells and induces FcγRIIB-
mediated apoptosis of CD8+ T cells. The goal of this research is to interrogate the mechanism by which Fgl2
regulates tumor-specific FcγRIIB+ CD8+ T cells using syngeneic mouse models via the following aim. AIM 1
(F99): Determine the cellular and molecular mechanism by which Fgl2 critically regulates tumor-specific
CD8+ T cells. Our studies show that both Foxp3+ regulatory T cells and CD8+ T cells express Fgl2 at the tumors
of mice and humans. Thus, we will determine if Fgl2 secreted by these cell types is necessary and/or sufficient
for FcγRIIB-mediated CD8+ T-cell apoptosis, findings which would provide the impetus for subsequent
therapeutic targeting of this cell type. Additionally, as we have discovered that FcγRIIB-Fgl2 binding induces
apoptosis, the upstream requirements of apoptosis (e.g. T-cell receptor stimulation, proteins recruited to the
intracellular domain of FcγRIIB) are proximal items of investigation in the latter part of Aim 1. Piecing together
the pathway by which FcγRIIB induces apoptosis via Fgl2 could uncover a new CD8+ T cell pathway readily
harnessed for future immunotherapies. AIM 2 (K00): Identify novel mechanisms of T cell resistance to
cancer immunotherapy. After the F99 stage, I intend to transition to the K00 stage to begin postdoctoral studies.
Numerous studies highlight the role of elevated checkpoint molecule expression (PD-1, TIM-3) as well as
decreased proinflammatory cytokine production (IFNγ, TNF) in mediating resistance to ICB. The current
paradigm in cancer immunotherapy revolves around the suppressive impact of the tumor microenvironment on
T cells, but the existence and impact of immunosuppressive factors secreted by effector CD8+ T cells themselves
is incompletely understood. The impact of the proposed aims is consi...

## Key facts

- **NIH application ID:** 11142784
- **Project number:** 4K00CA284255-02
- **Recipient organization:** ALLEN INSTITUTE
- **Principal Investigator:** Kelsey Bennion
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $90,715
- **Award type:** 4N
- **Project period:** 2023-09-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11142784

## Citation

> US National Institutes of Health, RePORTER application 11142784, Interrogating the Fgl2-FcgRIIB axis: A novel mechanism mediating apoptosis of tumor-specific memory CD8+ T cells (4K00CA284255-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11142784. Licensed CC0.

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