Renal Cell Carcinoma (RCC) Tumors Display Large Expansion of Double Positive (DP) CD4+CD8+ T Cells With Expression of Exhaustion Markers
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 (TI...
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doaj-e80faafa91584f1aba7c64031aee64612020-11-24T21:13:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-11-01910.3389/fimmu.2018.02728416272Renal Cell Carcinoma (RCC) Tumors Display Large Expansion of Double Positive (DP) CD4+CD8+ T Cells With Expression of Exhaustion MarkersLaurence C. Menard0Paul Fischer1Bijal Kakrecha2Peter S. Linsley3Erik Wambre4Maochang C. Liu5Blake J. Rust6Deborah Lee7Becky Penhallow8Nataly Manjarrez Orduno9Steven G. Nadler10Translational Medicine, Bristol-Myers Squibb, Princeton, NJ, United StatesTranslational Medicine, Bristol-Myers Squibb, Princeton, NJ, United StatesTranslational Medicine, Bristol-Myers Squibb, Princeton, NJ, United StatesBenaroya Research Institute at Virginia Mason, Seattle, WA, United StatesBenaroya Research Institute at Virginia Mason, Seattle, WA, United StatesBenaroya Research Institute at Virginia Mason, Seattle, WA, United StatesBenaroya Research Institute at Virginia Mason, Seattle, WA, United StatesTranslational Medicine, Bristol-Myers Squibb, Princeton, NJ, United StatesTranslational Medicine, Bristol-Myers Squibb, Princeton, NJ, United StatesTranslational Medicine, Bristol-Myers Squibb, Princeton, NJ, United StatesTranslational Medicine, Bristol-Myers Squibb, Princeton, NJ, United StatesCheckpoint 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.https://www.frontiersin.org/article/10.3389/fimmu.2018.02728/fullrenal cell carcinoma (RCC)CD4+CD8+ T cellsT cell dysfunctionTIM-3PD-1clonal expansion |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Renal Cell Carcinoma (RCC) Tumors Display Large Expansion of Double Positive (DP) CD4+CD8+ T Cells With Expression of Exhaustion Markers Frontiers in Immunology renal cell carcinoma (RCC) CD4+CD8+ T cells T cell dysfunction TIM-3 PD-1 clonal expansion |
author_facet |
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 |
author_sort |
Laurence C. Menard |
title |
Renal Cell Carcinoma (RCC) Tumors Display Large Expansion of Double Positive (DP) CD4+CD8+ T Cells With Expression of Exhaustion Markers |
title_short |
Renal Cell Carcinoma (RCC) Tumors Display Large Expansion of Double Positive (DP) CD4+CD8+ T Cells With Expression of Exhaustion Markers |
title_full |
Renal Cell Carcinoma (RCC) Tumors Display Large Expansion of Double Positive (DP) CD4+CD8+ T Cells With Expression of Exhaustion Markers |
title_fullStr |
Renal Cell Carcinoma (RCC) Tumors Display Large Expansion of Double Positive (DP) CD4+CD8+ T Cells With Expression of Exhaustion Markers |
title_full_unstemmed |
Renal Cell Carcinoma (RCC) Tumors Display Large Expansion of Double Positive (DP) CD4+CD8+ T Cells With Expression of Exhaustion Markers |
title_sort |
renal cell carcinoma (rcc) tumors display large expansion of double positive (dp) cd4+cd8+ t cells with expression of exhaustion markers |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2018-11-01 |
description |
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. |
topic |
renal cell carcinoma (RCC) CD4+CD8+ T cells T cell dysfunction TIM-3 PD-1 clonal expansion |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2018.02728/full |
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