Expression of LAG-3 defines exhaustion of intratumoral PD-1+ T cells and correlates with poor outcome in follicular lymphoma

Zhi Zhang Yang, Hyo Jin Kim, Jose C. Villasboas, Ya Ping Chen, Tammy P. Price-Troska, Shahrzad Jalali, Mara Wilson, Anne J. Novak, Stephen M. Ansell

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27 Citations (Scopus)

Abstract

Exhausted T-cells in follicular lymphoma (FL) typically express PD-1, but expression of PD-1 is not limited to exhausted cells. Although expected to be functionally suppressed, we found that the population of intratumoral PD-1+ T cells were predominantly responsible for production of cytokines and granules. This surprising finding prompted us to explore the involvement of LAG-3 to specifically identify functionally exhausted T cells. We found that LAG-3 was expressed on a subset of intratumoral T cells from FL and LAG-3+ T cells almost exclusively came from PD-1+ population. CyTOF analysis revealed that intratumoral LAG-3+ T cells were phenotypically heterogeneous as LAG-3 was expressed on a variety of T cell subsets. In contrast to PD-1+LAG-3- cells, intratumoral PD-1+LAG-3+ T cells exhibited reduced capacity to produce cytokines and granules. LAG-3 expression could be substantially upregulated on CD4+ or CD8+ T cells by IL-12, a cytokine that has been shown to induce T-cell exhaustion and be increased in the serum of lymphoma patients. Furthermore, we found that blockade of both PD-1 and LAG-3 signaling enhanced the function of intratumoral CD8+ T cells resulting in increased IFN-γ and IL-2 production. Clinically, LAG-3 expression on intratumoral T cells correlated with a poor outcome in FL patients. Taken together, we find that LAG-3 expression is necessary to identify the population of intratumoral PD-1+ T cells that are functionally exhausted and, in contrast, find that PD-1+LAG-3- T cells are simply activated cells that are immunologically functional. These findings may have important implications for immune checkpoint therapy in FL.

Original languageEnglish
Pages (from-to)61425-61439
Number of pages15
JournalOncotarget
Volume8
Issue number37
DOIs
Publication statusPublished - 2017 Sep 1

All Science Journal Classification (ASJC) codes

  • Oncology

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    Yang, Z. Z., Kim, H. J., Villasboas, J. C., Chen, Y. P., Price-Troska, T. P., Jalali, S., Wilson, M., Novak, A. J., & Ansell, S. M. (2017). Expression of LAG-3 defines exhaustion of intratumoral PD-1+ T cells and correlates with poor outcome in follicular lymphoma. Oncotarget, 8(37), 61425-61439. https://doi.org/10.18632/oncotarget.18251