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Title: Organotypic breast tumor model elucidates dynamic remodeling of tumor microenvironment
Authors:
; ; ; ; ; ;
Award ID(s):
1801591
Publication Date:
NSF-PAR ID:
10171503
Journal Name:
Biomaterials
Volume:
238
Issue:
C
Page Range or eLocation-ID:
119853
ISSN:
0142-9612
Sponsoring Org:
National Science Foundation
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  1. The killing of tumor cells by CD8+T cells is suppressed by the tumor microenvironment, and increased expression of inhibitory receptors, including programmed cell death protein-1 (PD-1), is associated with tumor-mediated suppression of T cells. To find cellular defects triggered by tumor exposure and associated PD-1 signaling, we established an ex vivo imaging approach to investigate the response of antigen-specific, activated effector CD8+tumor-infiltrating lymphocytes (TILs) after interaction with target tumor cells. Although TIL–tumor cell couples readily formed, couple stability deteriorated within minutes. This was associated with impaired F-actin clearing from the center of the cellular interface, reduced Ca2+signaling, increased TIL locomotion, and impaired tumor cell killing. The interaction of CD8+T lymphocytes with tumor cell spheroids in vitro induced a similar phenotype, supporting a critical role of direct T cell–tumor cell contact. Diminished engagement of PD-1 within the tumor, but not acute ex vivo blockade, partially restored cell couple maintenance and killing. PD-1 thus contributes to the suppression of TIL function by inducing a state of impaired subcellular organization.