Research ArticleCancer Immunology

PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and target tumor cells within the tumor

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Science Signaling  15 Sep 2020:
Vol. 13, Issue 649, eaau4518
DOI: 10.1126/scisignal.aau4518

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Keeping lymphocytes and tumor cells apart

When cytotoxic T cells enter tumors and become tumor-infiltrating lymphocytes (TILs), they lose their ability to kill target tumor cells. TILs in this state express inhibitory receptors, including PD-1, which are engaged in the tumor environment. Ambler et al. performed imaging analysis of mouse TILs ex vivo and showed that the suppressed cells had defective Ca2+ signaling, impaired cytoskeletal rearrangements, and a decreased ability to form productive contacts with their targets. Blocking PD-1 signaling in vivo, but not in vitro, restored these defects, stabilized the interactions between tumor cells and TILs, and improved cell killing.

Abstract

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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