Journal
SCIENCE SIGNALING
Volume 13, Issue 649, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aau4518
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Funding
- Wellcome Trust [102387/Z/13/Z, 201254/Z/16/Z]
- Biotechnology and Biological Sciences Research Council [BB/P011578/1-15]
- European Research Council [PCIG11-GA-2012-321554]
- U.S. NSF [MCB1616492]
- U.S. NIH [P41 GM103712]
- AstraZeneca, UK
- BBSRC [BB/P011578/1] Funding Source: UKRI
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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.
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