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

doi:10.1016/j.isci.2023.106443

CX3CR1 deficiency-induced TIL tumor restriction as a novel addition for CAR-T design in solid malignancies

iScience. 2023 Mar 21;26(4):106443. doi: 10.1016/j.isci.2023.106443. eCollection 2023 Apr 21.

Authors

ThuLe Trinh¹, William A Adams¹, Alexandra Calescibetta¹, Nhan Tu¹, Robert Dalton¹, Tina So¹, Max Wei¹, Grace Ward^{1

2}, Elena Kostenko¹, Sean Christiansen¹, Ling Cen³, Amy McLemore⁴, Kayla Reed¹, Junmin Whitting², Danielle Gilvary¹, Neale Lopez Blanco¹, Carlos Moran Segura¹, Jonathan Nguyen¹, Wendy Kandell^{1

2}, Xianghong Chen¹, Pingyan Cheng¹, Gabriela M Wright⁵, W Douglas Cress⁵, Jinghong Liu⁶, Kenneth L Wright¹, Sheng Wei¹, Erika A Eksioglu¹

Affiliations

¹ Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
² Cancer Biology PhD Program, University of South Florida and H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
³ Bioinformatics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁴ Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁵ Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁶ Department of Anesthesiology, Moffitt Cancer Center, Tampa, FL, USA.

Abstract

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.

Keywords: Cancer; Immunology; Oncology.