Navigating the Fas lane to improved cellular therapy for cancer
Madhav V. Dhodapkar
Madhav V. Dhodapkar
Published February 25, 2019
Citation Information: J Clin Invest. 2019;129(4):1522-1523. https://doi.org/10.1172/JCI127581.
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Navigating the Fas lane to improved cellular therapy for cancer

Abstract

Genetically engineered T cells have shown promising activity in the treatment of cancer. However, these cells are also potentially susceptible to immune-suppressive pathways in the tumor microenvironment that may limit their efficacy. In this issue of the JCI, Yamamoto et al. describe a new cellular engineering approach to prevent Fas-mediated inhibition of T cell function, which may be exploited to improve cellular therapy for cancer.

Authors

Madhav V. Dhodapkar

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Figure 1

Schematic representation of Fas signaling in tumor cells during CAR T cell therapy.

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Schematic representation of Fas signaling in tumor cells during CAR T ce...
(A) FasL-mediated inhibition of adoptive cell transfer. The apoptosis-inducing ligand FasL is preferentially expressed on tumor cells. T cells used for adoptive immunotherapy constitutively express Fas, the receptor for FasL. Cognate Fas-FasL interaction limits T cell persistence and ultimately affects antitumor efficacy. (B) Overcoming FasL-mediated inhibition. Genetically engineered dominant-negative Fas variants impair Fas-FasL binding and prevent FasL-induced apoptosis. This leads to longer persistence of T cells and to better tumor regression and enhanced survival. Figure illustrated by Rachel Davidowitz.