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

Journal volume & issue
Vol. 26, no. 4
p. 106443

Abstract

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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.

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