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Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
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Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells

Published on: February 8, 2018

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

Julien Fourcade1, Zhaojun Sun, Mourad Benallaoua

  • 1Department of Medicine and Division of Hematology/Oncology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.

The Journal of Experimental Medicine
|September 8, 2010
PubMed

Insights

In advanced melanoma, dual blockade of Tim-3/Tim-3L and PD-1/PD-L1 pathways can reverse T cell exhaustion. This combination therapy enhances the functional capacity of tumor-specific CD8(+) T cells, offering a promising strategy for cancer treatment.

Area of Science:

  • Immunology
  • Cancer Biology
  • Oncology

Background:

  • Spontaneous anti-tumor immune responses coexist with disease progression in cancer patients, highlighting T cell dysfunction.
  • In advanced melanoma, NY-ESO-1 specific CD8(+) T cells upregulate PD-1 upon chronic antigen stimulation.
  • PD-1 expression is linked to T cell dysfunction and impaired expansion in melanoma patients.

Purpose of the Study:

  • To investigate the role of Tim-3 expression in NY-ESO-1 specific CD8(+) T cells in advanced melanoma.
  • To assess the impact of Tim-3 and PD-1 co-expression on T cell dysfunction.
  • To evaluate the therapeutic potential of combined Tim-3/Tim-3L and PD-1/PD-L1 blockade in restoring T cell function.

Main Methods:

  • Flow cytometry analysis of T cell markers (PD-1, Tim-3) on NY-ESO-1 specific CD8(+) T cells.
  • Assessment of cytokine production (IFN-γ, TNF, IL-2) by T cells.
  • Ex vivo blockade of Tim-3/Tim-3L and PD-1/PD-L1 pathways and evaluation of T cell responses.

Main Results:

  • A subset of PD-1(+) NY-ESO-1 specific CD8(+) T cells also expressed Tim-3.
  • Tim-3(+)PD-1(+) CD8(+) T cells exhibited greater dysfunction, producing less cytokines compared to other subsets.
  • Tim-3/Tim-3L blockade alone or in synergy with PD-1/PD-L1 blockade enhanced T cell cytokine production and proliferation.

Conclusions:

  • Tim-3 expression identifies a more dysfunctional subset of tumor-specific T cells in advanced melanoma.
  • Combined blockade of Tim-3/Tim-3L and PD-1/PD-L1 pathways can overcome T cell exhaustion.
  • This dual blockade strategy holds promise for reversing tumor-induced T cell dysfunction in melanoma.

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