Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients

By J. Fourcade, Zhaojun Sun, M. Benallaoua, P. Guillaume, I. Luescher, C. Sander, J. Kirkwood, V. Kuchroo, H. Zarour. Journal of Experimental Medicine, 2010

1,304 citations recorded by the source corpus.

The paradoxical coexistence of spontaneous tumor antigen–specific immune responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction. In patients with advanced melanoma, we have previously shown that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1–specific CD8+ T cells that up-regulate PD-1 expression. We also observed that PD-1 regulates NY-ESO-1–specific CD8+ T cell expansion upon chronic antigen stimulation. In the present study, we show that a fraction of PD-1+ NY-ESO-1–specific CD8+ T cells in patients with advanced melanoma up-regulates Tim-3 expression and that Tim-3+PD-1+ NY-ESO-1–specific CD8+ T cells are more dysfunctional than Tim-3−PD-1+ and Tim-3−PD-1− NY-ESO-1–specific CD8+ T cells, producing less IFN-γ, TNF, and IL-2. Tim-3–Tim-3L blockade enhanced cytokine production by NY-ESO-1–specific CD8+ T cells upon short ex vivo stimulation with cognate peptide, thus enhancing their functional capacity. In addition, Tim-3–Tim-3L blockade enhanced cytokine production and proliferation of NY-ESO-1–specific CD8+ T cells upon prolonged antigen stimulation and acted in synergy with PD-1–PD-L1 blockade. Collectively, our findings support the use of Tim-3–Tim-3L blockade together with PD-1–PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/0e9c4b9eb49a8297b1a124fbad05e78e75dcd394

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Citations in the corpus

Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors. (2016, neutral): “PD-1, like CTLA-4, is expressed on activated T cells, and its activation hasbeen shown todownregulate signalingmediated on antigen recognition by the T cell receptor (Fourcade et al., 2010; Sakuishi et al., 2010; Sharma and Allison, 2015a; Woo et al., 2012; Zou et al., 2016).”
Tolerance and Exhaustion: Defining Mechanisms of T cell Dysfunction (2013, positive): “Animal studies and ex vivo studies with human tumorreactive T cells have demonstrated that combination checkpoint blockades, for example, PD-1+CTLA-4 [116], PD-1+LAG-3 [103], PD-1+TIM-3 [104,117], or PD-1+LAG3+CTLA-4 [118] may be required in some settings for rescue of T cell function and/or effecti”
T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment (2013, background): “In addition to low expression of CD28, high expression of Tim-3, CD57, killer cell lectin-like receptor subfamily G, member 1 (KLRG-1) are thought to be associated with T cell senescence [40,60,61 ,62,63 ,64] (Figure 2).”
Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy (2018, positive): “…cells in T cell high tumors is in keeping with the more antigen-experienced tumorreactive T cell populations described in other tumor types (Ahmadzadeh et al., 2009; Fourcade et al., 2010) and yet is only revealed in PDA when using these clonal tumor cell lines with dichotomous immune infiltration.”