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T Cell Exhaustion

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Front. Immunol. | doi: 10.3389/fimmu.2018.02728

Renal Cell Carcinoma (RCC) Tumors Display Large Expansion of Double Positive (DP) CD4+CD8+ T cells with Expression of Exhaustion Markers

 Laurence C. Menard1*, Paul Fischer1, Bijal Kakrecha1, Peter S. Linsley2,  Erik Wambre2, Maochang C. Liu2,  Blake Rust3,  Deborah Lee1, Becky Penhallow1,  Nataly Manjarrez Orduno1 and  Steven G. Nadler1
  • 1Bristol Myers Squibb (United States), United States
  • 2Benaroya Research Institute, United States
  • 3Fred Hutchinson Cancer Research Center, United States

Checkpoint inhibitors target the inhibitory receptors expressed by tumor-infiltrating T cells in order to reinvigorate an anti-tumor immune response. Therefore, understanding T cell composition and phenotype in human tumors is crucial. We analyzed by flow cytometry tumor-infiltrating lymphocytes (TILs) from two independent cohorts of patients with different cancer types, including RCC, lung and colon cancer. In healthy donors, peripheral T cells are usually either CD4+ or CD8+ with a small percentage of CD4+ CD8+ DP cells (<5%). Compared to several other cancer types, including lung and colorectal cancers, TILs from about a third of RCC patients showed an increased proportion of DP CD4+CD8+ T cells (>5%, reaching 30-50% of T cells in some patients). These DP T cells have an effector memory phenotype and express CD38, 4-1BB and HLA-DR, suggesting antigen-driven expansion. In fact, TCR sequencing analysis revealed a high degree of clonality in DP T cells. Additionally, there were high levels of PD-1 and TIM-3 expression on DP T cells, which correlated with higher expression of PD-1 and TIM-3 in conventional single positive CD8 T cells from the same patients. These results suggest that DP T cells could be dysfunctional tumor-specific T cells with the potential to be reactivated by checkpoint inhibitors.

Keywords: Renal cell carcinoma (RCC), CD4+CD8+ T cells, TIM-3, PD-1, Clonal expansion, T cell dysfunction

Received: 27 Jul 2018; Accepted: 05 Nov 2018.

Edited by:

Cristina Bonorino, Pontifícia Universidade Católica do Rio Grande do Sul, Brazil

Reviewed by:

Tomasz Zal, University of Texas MD Anderson Cancer Center, United States
Umaimainthan Palendira, Centenary Institute Australia, Australia  

Copyright: © 2018 Menard, Fischer, Kakrecha, Linsley, Wambre, Liu, Rust, Lee, Penhallow, Manjarrez Orduno and Nadler. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Laurence C. Menard, Bristol Myers Squibb (United States), New York, United States,