GRP78-CAR T cell effector function against solid and brain tumors is controlled by GRP78 expression on T cells

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• T-cell based immunotherapies face limitations due to a lack of targetable antigens.
• The unfolded protein response (UPR) pathway is crucial for cancer cell survival, proliferation, and metastasis.
• Glucose-regulated protein 78 (GRP78), a key UPR regulator, is overexpressed and present on the cell surface of many cancers.

Purpose of the Study:

• To evaluate cell surface GRP78 as a target for chimeric antigen receptor (CAR) T-cell immunotherapy.
• To assess the efficacy of GRP78-specific CAR T-cells against solid and brain tumors.

Main Methods:

• Characterization of GRP78 expression on various solid and brain tumor cell lines.
• Development and testing of GRP78-specific CAR T-cells in vitro and in vivo models.
• Analysis of GRP78 expression dynamics on CAR T-cells post-activation.

Main Results:

• Cell surface GRP78 is highly expressed across multiple solid and brain tumors.
• GRP78-CAR T-cells effectively recognized and eliminated GRP78-positive tumors in vitro and in vivo.
• GRP78 upregulation on CAR T-cells post-activation was observed, but this was tumor-cell-line specific.

Conclusions:

• Cell surface GRP78 is a promising target for developing novel CAR T-cell therapies for various cancers.
• GRP78-CAR T-cells demonstrate therapeutic potential against GRP78-expressing tumors.
• Tumor-specific heterogeneity in GRP78 expression may influence CAR T-cell therapeutic response.