Cell-Surface GRP78-Targeted Chimeric Antigen Receptor T Cells Eliminate Lung Cancer Tumor Xenografts

Abstract

Lung cancer is one of the most common and intractable malignancies. It is associated with low survival rates despite existing treatments, indicating that new and more effective therapies are urgently needed such as the chimeric antigen receptor-T (CAR-T) cell immunotherapy. The cell-surface glucose-regulated protein 78 (csGRP78) is expressed in various hematological malignancies and solid tumor cells including lung cancer in response to cancer-related endoplasmic reticulum stress, while GRP78 is restricted to inside the normal cells. Here, we detected the prominent expression of csGRP78 in both lung cancer cell lines, A549 and H1299, as well as cancer stemlike cells derived from A549 by immunofluorescence. Next, a csGRP78-targeted CAR was constructed, and the transduced CAR-T cells were tested for their potency to kill the two lung cancer cell lines and derived stemlike cells, which was correlated with specific interferon γ release in vitro. Finally, we found that csGRP78 CAR-T cells also efficiently killed both lung cancer cells and cancer stemlike cells, resulting into the elimination of tumor xenografts in vivo, neither with any evidence of relapse after 63 days of tumor clearance nor any detrimental impact on other body organs we examined. Our study reveals the capacity of csGRP78 as a therapeutic target and offers valuable insight into the development of csGRP78 CAR-T cells as potential therapy for lung cancer.

Diversity of extracellular HSP70 in cancer: advancing from a molecular biomarker to a novel therapeutic target

“…AKT, kinase-protein kinase B; ERK1/2, extracellular regulated protein kinases 1/2; MAPK, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; PDAC, pancreatic ductal adenocarcinoma; YAP, Yes-associated protein; TAZ, tafazzin; PI3K, promoting phosphatidylinositol 3; CHM-1, 2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone; NPC, nasopharyngeal carcinoma; FMBP, a class III secretory peroxidase derived from foxtail millet bran; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; ISM, isthmin; AMOP, adhesion-associated domain in MUC4 and other proteins; HUVEC, human umbilical vein endothelial cell; TLR2, toll-like receptor 2; MDSCs, myeloid-derived suppressive cells. several solid tumors, such as pancreatic cancer, lung cancer, glioblastoma, and breast cancer, without obvious off-target effects or T cell infiltration in major organs (206)(207)(208)(209)(210)(211)(212). Moreover, several researchers have combined HSP70 binding peptide with other anticancer proteins or encased it within nanoparticles to precisely and effectively deliver chemotherapeutic drugs (213)(214)(215)(216)(217)(218)(219)(220).…”