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

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 considerable as they will identify novel targets, that could rescue a population of memory CD8+ T cells that are crucial to the immune response to tumor.