Genetic Modification of CD8+ T Cells to Express EGFR: Potential Application for Adoptive T Cell Therapies

Abstract

Adoptive immunotherapy with ex vivo-expanded tumor-infiltrating lymphocytes (TILs) has achieved objective clinical responses in a significant number of patients with cancer. The failure of many patients to develop long-term tumor control may be, in part, due to exhaustion of transferred T cells in the presence of a hostile tumor microenvironment. In several tumor types, growth and survival of carcinoma cells appear to be sustained by a network of receptors/ligands of the ErbB family. We speculated that if transferred T cells could benefit from EGFR ligands produced by the tumor, they might proliferate better and exert their anti-tumor activities more efficiently. We found that CD8 + T cells transduced with a retrovirus to express EGFR responded to EGFR ligands activating the EGFR signaling pathway. These EGFR-expressing effector T cells proliferated better and produced more IFN-γ and TNF-α in the presence of EGFR ligands produced by tumor cells in vitro. EGFR-expressing CD8 T cells from OT-1 mice were more efficient killing B16-OVA cells than control OT-1 CD8 T cells. Importantly, EGFR-expressing OT-1 T cells injected into B16-OVA tumor bearing mice were recruited into the tumor, expressed lower levels of the exhaustion markers PD1, TIGIT, and LAG3, and were more efficient in delaying tumor growth. Our results suggest that genetic modification of CD8 + T cells to express EGFR might be considered in immunotherapeutic strategies based on adoptive transfer of anti-tumor T cells against cancers expressing EGFR ligands.

Colorectal cancer cells promote osteoclastogenesis and bone destruction through regulating EGF/ERK/CCL3 pathway

“…Recent one study indicated the EGF can be efficiently produced in MC-38 cells and EGF could activate the ERK pathway [15,16], thus we next explored whether MC-38-derived EGF contributed to the overexpression of CCL3 through ERK pathway. Interestingly, the activation of ERK1/2 was prevented in BMMs cultured in CM after treatment with EGF neutralizing antibody (Figure 5A,B).…”

Construction of Protein-related Risk Score Model in Bladder Urothelial Carcinoma

“…However, in the present study, AXL was strong and positively correlated to CD8+ T cell from Figure 12(a). CD8+ T cells expressing EGFR could benefit from EGFR ligands produced by the tumor [23]. EGFR is beneficial to CD8+ T cells in bladder cancer.…”

TIPS: Trajectory Inference of Pathway Significance through Pseudotime Comparison for Functional Assessment of single-cell RNAseq Data

“…From further exploration of the unannotated cluster, we found that the cluster was dominated by ribosomal signatures, explaining the inclusion of significant correlations with ribosome-related pathways in our inference (FigS5). More interestingly however, we also uncovered pathways that have been reported to influence CD8+ T cell behavior in other contexts, such as the ROBO receptors and ERBB2 signaling pathways [26][27]. These pathways largely underwent substantial changes in gene expression early on in the pseudotime trajectory, although a portion of the ROBO receptor pathway shifted later on (Fig4F).…”