iScience (Apr 2023)
CX3CR1 deficiency-induced TIL tumor restriction as a novel addition for CAR-T design in solid malignancies
- ThuLe Trinh,
- William A. Adams,
- Alexandra Calescibetta,
- Nhan Tu,
- Robert Dalton,
- Tina So,
- Max Wei,
- Grace Ward,
- Elena Kostenko,
- Sean Christiansen,
- Ling Cen,
- Amy McLemore,
- Kayla Reed,
- Junmin Whitting,
- Danielle Gilvary,
- Neale Lopez Blanco,
- Carlos Moran Segura,
- Jonathan Nguyen,
- Wendy Kandell,
- Xianghong Chen,
- Pingyan Cheng,
- Gabriela M. Wright,
- W. Douglas Cress,
- Jinghong Liu,
- Kenneth L. Wright,
- Sheng Wei,
- Erika A. Eksioglu
Affiliations
- ThuLe Trinh
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- William A. Adams
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Alexandra Calescibetta
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Nhan Tu
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Robert Dalton
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Tina So
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Max Wei
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Grace Ward
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Cancer Biology PhD Program, University of South Florida and H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Elena Kostenko
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Sean Christiansen
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Ling Cen
- Bioinformatics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Amy McLemore
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Kayla Reed
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Junmin Whitting
- Cancer Biology PhD Program, University of South Florida and H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Danielle Gilvary
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Neale Lopez Blanco
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Carlos Moran Segura
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Jonathan Nguyen
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Wendy Kandell
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Cancer Biology PhD Program, University of South Florida and H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Xianghong Chen
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Pingyan Cheng
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Gabriela M. Wright
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- W. Douglas Cress
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Jinghong Liu
- Department of Anesthesiology, Moffitt Cancer Center, Tampa, FL, USA
- Kenneth L. Wright
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Sheng Wei
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Erika A. Eksioglu
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Corresponding author
- Journal volume & issue
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Vol. 26,
no. 4
p. 106443
Abstract
Summary: Advances in the understanding of the tumor microenvironment have led to development of immunotherapeutic strategies, such as chimeric antigen receptor T cells (CAR-Ts). However, despite success in blood malignancies, CAR-T therapies in solid tumors have been hampered by their restricted infiltration. Here, we used our understanding of early cytotoxic lymphocyte infiltration of human lymphocytes in solid tumors in vivo to investigate the receptors in normal, adjacent, and tumor tissues of primary non-small-cell lung cancer specimens. We found that CX3CL1-CX3CR1 reduction restricts cytotoxic cells from the solid-tumor bed, contributing to tumor escape. Based on this, we designed a CAR-T construct using the well-established natural killer group 2, member D (NKG2D) CAR-T expression together with overexpression of CX3CR1 to promote their infiltration. These CAR-Ts infiltrate tumors at higher rates than control-activated T cells or IL-15-overexpressing NKG2D CAR-Ts. This construct also had similar functionality in a liver-cancer model, demonstrating potential efficacy in other solid malignancies.
