Renal cell carcinoma (RCC) tumors display large expansion of double positive (DP) CD4+CD8+ T cells with expression of exhaustion markers

Laurence C. Menard, Paul Fischer, Bijal Kakrecha, Peter S. Linsley, Erik Wambre, Maochang C. Liu, Blake J. Rust, Deborah Lee, Becky Penhallow, Nataly Manjarrez Orduno, Steven G. Nadler

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

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.

Original languageEnglish
Article number2728
JournalFrontiers in Immunology
Volume9
Issue numberNOV
DOIs
StatePublished - 26 Nov 2018
Externally publishedYes

Keywords

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

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