Related Experiment Video
Updated: Jun 3, 2026
Monitoring PD-1-Blocking Antibodies Bound to T Cells Derived from a Drop of Peripheral Blood
Published on: February 5, 2020
Early T cell signalling is reversibly altered in PD-1+ T lymphocytes infiltrating human tumors
Shu-Fang Wang1, Stéphane Fouquet, Maxime Chapon
1Inserm, U1016, Institut Cochin, Paris, France.
Abstract:
To improve cancer immunotherapy, a better understanding of the weak efficiency of tumor-infiltrating T lymphocytes (TIL) is necessary. We have analyzed the functional state of human TIL immediately after resection of three types of tumors (NSCLC, melanoma and RCC). Several signalling pathways (calcium, phosphorylation of ERK and Akt) and cytokine secretion are affected to different extents in TIL, and show a partial spontaneous recovery within a few hours in culture. The global result is an anergy that is quite distinct from clonal anergy induced in vitro, and closer to adaptive tolerance in mice. PD-1 (programmed death -1) is systematically expressed by TIL and may contribute to their anergy by its mere expression, and not only when it interacts with its ligands PD-L1 or PD-L2, which are not expressed by every tumor. Indeed, the TCR-induced calcium and ERK responses were reduced in peripheral blood T cells transfected with PD-1. Inhibition by sodium stibogluconate of the SHP-1 and SHP-2 phosphatases that associate with several inhibitory receptors including PD-1, relieves part of the anergy apparent in TIL or in PD-1-transfected T cells. This work highlights some of the molecular modifications contributing to functional defects of human TIL.
Insights
Tumor-infiltrating lymphocytes (TIL) show anergy, a state of unresponsiveness, hindering cancer immunotherapy. PD-1 expression on TIL contributes to this anergy, suggesting new therapeutic targets.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Cancer immunotherapy efficacy is limited by the poor function of tumor-infiltrating lymphocytes (TIL).
- Understanding the molecular basis of TIL dysfunction is crucial for developing effective cancer treatments.
Purpose of the Study:
- To investigate the functional state and molecular mechanisms underlying the anergy of human TIL from non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC).
- To explore the role of programmed death-1 (PD-1) and associated phosphatases in TIL anergy.
Main Methods:
- Analysis of signaling pathways (calcium, ERK, Akt) and cytokine secretion in human TIL post-resection.
- Assessment of PD-1 expression and its impact on T cell responses.
- Inhibition of SHP-1 and SHP-2 phosphatases using sodium stibogluconate to evaluate their role in TIL anergy.
Main Results:
- Human TIL exhibit an anergic state with altered signaling pathways and cytokine secretion, distinct from in vitro induced anergy.
- PD-1 is consistently expressed on TIL and may induce anergy intrinsically, independent of ligand binding.
- Inhibition of SHP-1/SHP-2 phosphatases partially reversed TIL anergy and the functional defects in PD-1-expressing T cells.
Conclusions:
- Human TIL possess a unique anergic phenotype contributing to their functional impairment in the tumor microenvironment.
- PD-1 expression is a significant factor in TIL anergy, offering a potential therapeutic target.
- Targeting SHP-1/SHP-2 phosphatases may represent a strategy to restore TIL function in cancer immunotherapy.
Related Concept Videos
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:23Abnormal Proliferation