ProS1-MerTK signaling in CD4 T cells: implications for TIL expansion and functionality

Area of Science:

• Immunology
• Cancer Biology
• Cellular Therapy

Background:

• Adoptive cell therapy (ACT) primarily focuses on CD8 T cells, but CD4 T cells are increasingly recognized for their critical role.
• The MerTK receptor (MerTK) influences immune responses and CD8 T cell costimulation, yet its function in CD4 T cells is largely unknown.
• Understanding CD4 T cell regulation is vital for advancing cancer immunotherapy strategies.

Purpose of the Study:

• To investigate the role and therapeutic potential of ProS1-MerTK signaling in CD4 T cell function.
• To elucidate the impact of ProS1-MerTK on CD4 T cell memory, metabolism, and polarization.
• To assess the utility of ProS1 in enhancing tumor-infiltrating lymphocytes (TILs) for ACT.

Main Methods:

• Analysis of ProS1-MerTK signaling in activated CD4 T cells.
• CRISPR-Cas9 gene editing to assess the function of MerTK.
• In vitro expansion of tumor-infiltrating lymphocytes (TILs) with ProS1 for ACT.

Main Results:

• ProS1-MerTK signaling is upregulated in activated CD4 T cells, promoting memory formation, metabolic fitness, and proliferation.
• MerTK deficiency impairs CD4 T cell fitness, function, and type 1 immune response polarization.
• ProS1 addition during TIL expansion enhanced CD4 T cell stemness, memory phenotypes, and helper functions while reducing exhaustion.

Conclusions:

• ProS1-MerTK signaling is a key pathway regulating CD4 T cell functionality and type 1 immune responses.
• Targeting ProS1-MerTK signaling can enhance CD4 T cell properties favorable for ACT.
• This pathway presents a promising therapeutic strategy to improve outcomes in TIL-based ACT for advanced melanoma.