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Cancer Res. 2017 Jul 1;77(13):3672-3684. doi: 10.1158/0008-5472.CAN-17-0236. Epub 2017 May 18.

Expansion of Tumor-Infiltrating CD8+ T cells Expressing PD-1 Improves the Efficacy of Adoptive T-cell Therapy.

Author information

1
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Navarra, Spain.
2
Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarra, Spain.
3
Oncology Department, University Clinic, University of Navarra, Navarra, Spain.
4
Centre for Nutrition Research, University of Navarra, Navarra, Spain.
5
Cytometry Unit, CIMA, University of Navarra, Navarra, Spain.
6
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Navarra, Spain. mshervas@unav.es.

Abstract

Recent studies have found that tumor-infiltrating lymphocytes (TIL) expressing PD-1 can recognize autologous tumor cells, suggesting that cells derived from PD-1+ TILs can be used in adoptive T-cell therapy (ACT). However, no study thus far has evaluated the antitumor activity of PD-1-selected TILs in vivo In two mouse models of solid tumors, we show that PD-1 allows identification and isolation of tumor-specific TILs without previous knowledge of their antigen specificities. Importantly, despite the high proportion of tumor-reactive T cells present in bulk CD8 TILs before expansion, only T-cell products derived from sorted PD-1+, but not from PD-1- or bulk CD8 TILs, specifically recognized tumor cells. The fold expansion of PD-1+ CD8 TILs was 10 times lower than that of PD-1- cells, suggesting that outgrowth of PD-1- cells was the limiting factor in the tumor specificity of cells derived from bulk CD8 TILs. The highly differentiated state of PD-1+ cells was likely the main cause hampering ex vivo expansion of this subset. Moreover, PD-1 precisely identified marrow-infiltrating, myeloma-specific T cells in a mouse model of multiple myeloma. In vivo, only cells expanded from PD-1+ CD8 TILs contained tumor progression, and their efficacy was enhanced by PDL-1 blockade. Overall, our data provide a rationale for the use of PD-1-selected TILs in ACT. Cancer Res; 77(13); 3672-84. ©2017 AACR.

PMID:
28522749
DOI:
10.1158/0008-5472.CAN-17-0236
[Indexed for MEDLINE]
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