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  • Open Access

Differential expression of PD-1 and Tim-3 marks activation versus exhaustion status of T cells in the tumor microenvironment

  • 1 and
  • 2
Journal for ImmunoTherapy of Cancer20142 (Suppl 3) :P220

https://doi.org/10.1186/2051-1426-2-S3-P220

  • Published:

Keywords

  • Tumor Microenvironment
  • Cancer Immunotherapy
  • Cell Exhaustion
  • Immune Checkpoint Receptor
  • Cellular Activation Status

Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are two immune checkpoint receptors (ICR) highly co-expressed on tumor infiltrating T lymphocytes (TIL). PD-1 has been shown to inhibit T cell activation and type 1 T cell responses, while Tim-3 has been proposed as a further marker of exhaustion on TIL [1, 2], leading us to investigate the phenotypic and functional characteristics of TIL with differential PD-1 and Tim-3 expression from head and neck cancer (HNC) patients. Our data showed that PD-1+Tim-3+ CD8+ and Foxp3- CD4+ TILs manifested high phosphorylated signal transducers and activators of transcription 1 (p-STAT1) and the associated Th1 transcription factor T-bet, which might correlate with T cell exhaustion, both at baseline and upon TCR stimulation. Moreover, the sorted PD-1+Tim-3+ CD8+ TILs expressed the lowest IFN-γ and TNF-α transcripts and the least amount of secreted IFN-γ upon TCR stimulation, indicating they are the most dysfunctional T cells in the tumor microenvironment (TME). Among CD4+CD25lo/- TIL subsets, PD-1hiTim-3- cells are more defective in terms of IFN-γ expression. Sorted PD-1intTim-3- CD8+ and CD4+CD25lo/- TILs showed higher TCR-stimulated expression of IFN-γ and TNF-α transcripts and secretion of IFN-γ, suggesting they are the most activated subsets. In addition, sorted PD-1+Tim-3+ and PD-1hiTim-3- TIL were less proliferative than other subsets, concomitant with lower expression of phosphorylated S6 (p-S6), while PD-1intTim-3-, PD-1-Tim-3+ and PD-1-Tim-3- TIL retained p-S6 activation or proliferation, suggesting that high expression of PD-1 on T cells interferes with TCR or Tim-3 signaling and associated cellular activation status. Taken together, PD-1+Tim-3+ and PD-1hiTim-3- TIL are most dysfunctional, while PD-1intTim-3- TIL are more activated in terms of both Th1 cytokine production and proliferation. These results provide a better understanding of the functional status of TIL subsets and roles of PD-1 and Tim-3 in regulating anti-tumor T cell response, as targets for cancer immunotherapy.

Authors’ Affiliations

(1)
Department of Pharmacy, School of Medicine, Tsinghua University, Beijing, Pittsburgh, PA, China, USA
(2)
University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

References

  1. Jin HT, Anderson AC, Tan WG et al.: Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proceedings of the National Academy of Sciences of the United States of America. 2010, 107: 14733-8. 10.1073/pnas.1009731107.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Fourcade J, Sun Z, Benallaoua M et al.: Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. The Journal of experimental medicine. 2010, 207: 2175-86. 10.1084/jem.20100637.PubMed CentralView ArticlePubMedGoogle Scholar

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