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

• Published in: iScience Vol. 26; no. 4; p. 106443
• Main Authors: Trinh, ThuLe, Adams, William A., Calescibetta, Alexandra, Tu, Nhan, Dalton, Robert, So, Tina, Wei, Max, Ward, Grace, Kostenko, Elena, Christiansen, Sean, Cen, Ling, McLemore, Amy, Reed, Kayla, Whitting, Junmin, Gilvary, Danielle, Blanco, Neale Lopez, Segura, Carlos Moran, Nguyen, Jonathan, Kandell, Wendy, Chen, Xianghong, Cheng, Pingyan, Wright, Gabriela M., Cress, W. Douglas, Liu, Jinghong, Wright, Kenneth L., Wei, Sheng, Eksioglu, Erika A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-04-2023; Elsevier
• Subjects: Cancer; Immunology; Oncology; Oncology; Immunology; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.106443

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.
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•Tumor establishment prevents infiltration of TILs, regardless of their survival•CX3CR1/CX3CL1 axis plays a major role in TIL infiltration and activity in solid tumors•Addition of CX3CR1 to NKG2D CAR-T enhanced infiltration and killing efficiency in vivo
Oncology; Immunology; Cancer