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

Teresa Lozano,Patricia Sarrión,Marina Ruiz De Galarreta,Noelia Casares,Silvia Chocarro,Sandra Hervás-Stubbs,Juan J Lasarte,Amaia Lujambio,Aritz Lasarte-Cia,Marta Gorraiz,Pablo Sarobe,Celia Martin,Cynthia Del Valle

doi:10.3389/fimmu.2019.02990

Teresa Lozano, Patricia Sarrión + Show 11 more

Open Access

https://doi.org/10.3389/fimmu.2019.02990

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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.

Highlights

Adoptive cell therapy (ACT) with ex vivo-expanded tumor-infiltrating lymphocytes (TILs) has achieved objective clinical responses in a significant fraction of patients with cancer [1]
We examined the expression of EGFR and EGFR ligands using Real-time PCR in murine tumor cell lines and confirmed the broad expression of EGFR in tumors from different origin
Regarding the EGFR ligands, we found that epidermal growth factor (EGF) was the predominant EGFR ligand in lymphoma, hepatocarcinoma, colon carcinoma, melanoma, breast cancer, myeloma and reticulum cell sarcoma cell lines (Figure 1A)

Summary

Introduction

Adoptive cell therapy (ACT) with ex vivo-expanded tumor-infiltrating lymphocytes (TILs) has achieved objective clinical responses in a significant fraction of patients with cancer [1]. The success of ACT is largely related to their capacity to infiltrate the tumor, persist in the host, and exert their anti-tumoral activity after their transfer. The failure of many patients to develop long-term tumor control may be, in part, due to exhaustion and apoptosis of the transferred T cells. The in vivo persistence of transferred T cells can vary from hours or days to weeks [2]. T cell persistence can depend largely on the manner in which T cells were expanded in vitro, the conditions of cell administration, and importantly, on the tumor microenvironment.

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