Enhanced Phenotype Definition for Precision Isolation of Precursor Exhausted Tumor-Infiltrating CD8 T Cells
In the context of adoptive T cell transfer (ACT) for cancer treatment, it is crucial to generate in vitro large amounts of tumor-specific CD8 T cells with high potential to persist in vivo. PD-1, Tim3, and CD39 have been proposed as markers of tumor-specific tumor-infiltrating CD8 T lymphocytes (CD8...
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doaj-ec28247533054f53bcf9e2ca8fe45d812020-11-24T23:58:43ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-02-011110.3389/fimmu.2020.00340519115Enhanced Phenotype Definition for Precision Isolation of Precursor Exhausted Tumor-Infiltrating CD8 T CellsAmaia Martinez-Usatorre0Santiago J. Carmona1Céline Godfroid2Céline Yacoub Maroun3Sara Labiano4Pedro Romero5Department of Oncology UNIL CHUV, University of Lausanne, Épalinges, SwitzerlandDepartment of Oncology UNIL CHUV, Ludwig Institute for Cancer Research, University of Lausanne, Épalinges, SwitzerlandDepartment of Oncology UNIL CHUV, University of Lausanne, Épalinges, SwitzerlandDepartment of Oncology UNIL CHUV, University of Lausanne, Épalinges, SwitzerlandDepartment of Oncology UNIL CHUV, University of Lausanne, Épalinges, SwitzerlandDepartment of Oncology UNIL CHUV, University of Lausanne, Épalinges, SwitzerlandIn the context of adoptive T cell transfer (ACT) for cancer treatment, it is crucial to generate in vitro large amounts of tumor-specific CD8 T cells with high potential to persist in vivo. PD-1, Tim3, and CD39 have been proposed as markers of tumor-specific tumor-infiltrating CD8 T lymphocytes (CD8 TILs). However, these molecules are highly expressed by terminally differentiated exhausted CD8 T cells (Tex) that lack proliferation potential. Therefore, optimized strategies to isolate tumor-specific TILs with high proliferative potential, such as Tcf1+ precursor exhausted T cells (Tpe) are needed to improve in vivo persistence of ACT. Here we aimed at defining cell surface markers that would unequivocally identify Types for precision cell sorting increasing the purity of tumor-specific PD-1+ Tcf1+ Tpe from total TILs. Transcriptomic analysis of Tpe vs. Tex CD8 TIL subsets from B16 tumors and primary human melanoma tumors revealed that Tpes are enriched in Slamf6 and lack Entpd1 and Havcr2 expression, which encode Slamf6, CD39, and Tim3 cell surface proteins, respectively. Indeed, we observed by flow cytometry that CD39– Tim3– Slamf6+ PD-1+ cells yielded maximum enrichment for tumor specific PD-1+ Tcf1+ OT1 TILs in B16.OVA tumors. Moreover, this population showed higher re-expansion capacity upon an acute infection recall response compared to the CD39+ counterparts or bulk PD-1+ TILs. Hence, we report an enhanced sorting strategy (CD39– Tim3– Slamf6+ PD-1+) of Tpes. In conclusion, we show that optimization of CD8 TIL cell sorting strategy is a viable approach to improve recall capacity and in vivo persistence of transferred cells in the context of ACT.https://www.frontiersin.org/article/10.3389/fimmu.2020.00340/fulltumor-infiltrating CD8 T cellsprecursor exhausted T cellsmemory-like CD8 T cellsadoptive cell transfermelanoma |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Amaia Martinez-Usatorre Santiago J. Carmona Céline Godfroid Céline Yacoub Maroun Sara Labiano Pedro Romero |
spellingShingle |
Amaia Martinez-Usatorre Santiago J. Carmona Céline Godfroid Céline Yacoub Maroun Sara Labiano Pedro Romero Enhanced Phenotype Definition for Precision Isolation of Precursor Exhausted Tumor-Infiltrating CD8 T Cells Frontiers in Immunology tumor-infiltrating CD8 T cells precursor exhausted T cells memory-like CD8 T cells adoptive cell transfer melanoma |
author_facet |
Amaia Martinez-Usatorre Santiago J. Carmona Céline Godfroid Céline Yacoub Maroun Sara Labiano Pedro Romero |
author_sort |
Amaia Martinez-Usatorre |
title |
Enhanced Phenotype Definition for Precision Isolation of Precursor Exhausted Tumor-Infiltrating CD8 T Cells |
title_short |
Enhanced Phenotype Definition for Precision Isolation of Precursor Exhausted Tumor-Infiltrating CD8 T Cells |
title_full |
Enhanced Phenotype Definition for Precision Isolation of Precursor Exhausted Tumor-Infiltrating CD8 T Cells |
title_fullStr |
Enhanced Phenotype Definition for Precision Isolation of Precursor Exhausted Tumor-Infiltrating CD8 T Cells |
title_full_unstemmed |
Enhanced Phenotype Definition for Precision Isolation of Precursor Exhausted Tumor-Infiltrating CD8 T Cells |
title_sort |
enhanced phenotype definition for precision isolation of precursor exhausted tumor-infiltrating cd8 t cells |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2020-02-01 |
description |
In the context of adoptive T cell transfer (ACT) for cancer treatment, it is crucial to generate in vitro large amounts of tumor-specific CD8 T cells with high potential to persist in vivo. PD-1, Tim3, and CD39 have been proposed as markers of tumor-specific tumor-infiltrating CD8 T lymphocytes (CD8 TILs). However, these molecules are highly expressed by terminally differentiated exhausted CD8 T cells (Tex) that lack proliferation potential. Therefore, optimized strategies to isolate tumor-specific TILs with high proliferative potential, such as Tcf1+ precursor exhausted T cells (Tpe) are needed to improve in vivo persistence of ACT. Here we aimed at defining cell surface markers that would unequivocally identify Types for precision cell sorting increasing the purity of tumor-specific PD-1+ Tcf1+ Tpe from total TILs. Transcriptomic analysis of Tpe vs. Tex CD8 TIL subsets from B16 tumors and primary human melanoma tumors revealed that Tpes are enriched in Slamf6 and lack Entpd1 and Havcr2 expression, which encode Slamf6, CD39, and Tim3 cell surface proteins, respectively. Indeed, we observed by flow cytometry that CD39– Tim3– Slamf6+ PD-1+ cells yielded maximum enrichment for tumor specific PD-1+ Tcf1+ OT1 TILs in B16.OVA tumors. Moreover, this population showed higher re-expansion capacity upon an acute infection recall response compared to the CD39+ counterparts or bulk PD-1+ TILs. Hence, we report an enhanced sorting strategy (CD39– Tim3– Slamf6+ PD-1+) of Tpes. In conclusion, we show that optimization of CD8 TIL cell sorting strategy is a viable approach to improve recall capacity and in vivo persistence of transferred cells in the context of ACT. |
topic |
tumor-infiltrating CD8 T cells precursor exhausted T cells memory-like CD8 T cells adoptive cell transfer melanoma |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2020.00340/full |
work_keys_str_mv |
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