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.
Highlights
One of the generally accepted reasons for which the immune system has a low efficacy for fighting cancers is that tumorinfiltrating lymphocytes (TIL) are dysfunctional, because of an immmunosuppressive tumor microenvironment, and because TIL express inhibitory receptors, like PD-1
T cell signalling are altered in human TIL The functional state of human TIL freshly isolated from three types of tumors (non-small cell lung carcinoma (NSCLC), melanoma and renal cell carcinoma (RCC)) has been investigated within a few hours after tumor resection
The phosphorylation of Akt induced by CD3/CD28 cross-linking was severely affected (,15 times reduction compared to Peripheral blood T cells (PBT), Fig. 1B) whereas levels of phosphorylated ERK was only 2 to 3 times reduced in TIL after 2 minutes of anti-CD3-activation (Fig. 1C)
Summary
One of the generally accepted reasons for which the immune system has a low efficacy for fighting cancers is that tumorinfiltrating lymphocytes (TIL) are dysfunctional, because of an immmunosuppressive tumor microenvironment, and because TIL express inhibitory receptors, like PD-1. PD-1 is a receptor expressed by cells that are chronically activated, for instance in chronic viral diseases such as HIV, and it appears to contribute to the exhausted state of these cells [1] These general notions are widely accepted, a closer look shows that the functional state of TIL remains ill-defined and would deserve a more stringent examination. It is inappropriate for evaluating the existence of alterations in early TCR signalling Both naıve and memory T cells show good responses in terms of early signalling with Ca or ERK as readouts; only effector/memory cells are able to secrete IFN-c after stimulation by PMA/ionomycin, revealing their distinct differentiation state. Several papers have shown that TIL are experienced T cells, as judged by their phenotype and their ability to respond to PMA/ionomycin [8,9], others have described a failure to respond to these stimuli [10,11]
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