RT Journal Article
SR Electronic
T1 4-1BB co-stimulation further enhances anti-PD-1-mediated reinvigoration of exhausted CD39<sup>+</sup> CD8 T cells from primary and metastatic sites of epithelial ovarian cancers
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e001650
DO 10.1136/jitc-2020-001650
VO 8
IS 2
A1 Galam Leem
A1 Junsik Park
A1 Minwoo Jeon
A1 Eui-Soon Kim
A1 Sang Wun Kim
A1 Yong Jae Lee
A1 Seong Jin Choi
A1 Baekgyu Choi
A1 Seongyeol Park
A1 Young Seok Ju
A1 Inkyung Jung
A1 Sunghoon Kim
A1 Eui-Cheol Shin
A1 Jung Yun Lee
A1 Su-Hyung Park
YR 2020
UL http://jitc.bmj.com/content/8/2/e001650.abstract
AB Background Responses to immunotherapy vary between different cancer types and sites. Here, we aimed to investigate features of exhaustion and activation in tumor-infiltrating CD8 T cells at both the primary and metastatic sites in epithelial ovarian cancer.Methods Tumor tissues and peripheral blood were obtained from 65 patients with ovarian cancer. From these samples, we isolated tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells. These cells were used for immunophenotype using multicolor flow cytometry, gene expression profile using RNA sequencing and ex vivo functional restoration assays.Results We found that CD39+ CD8 TILs were enriched with tumor-specific CD8 TILs, and that the activation status of these cells was determined by the differential programmed cell death protein 1 (PD-1) expression level. CD39+ CD8 TILs with high PD-1 expression (PD-1high) exhibited features of highly tumor-reactive and terminally exhausted phenotypes. Notably, PD-1high CD39+ CD8 TILs showed similar characteristics in terms of T-cell exhaustion and activation between the primary and metastatic sites. Among co-stimulatory receptors, 4-1BB was exclusively overexpressed in CD39+ CD8 TILs, especially on PD-1high cells, and 4-1BB-expressing cells displayed immunophenotypes indicating higher degrees of T-cell activation and proliferation, and less exhaustion, compared with cells not expressing 4-1BB. Importantly, 4-1BB agonistic antibodies further enhanced the anti-PD-1-mediated reinvigoration of exhausted CD8 TILs from both primary and metastatic sites.Conclusion Severely exhausted PD-1high CD39+ CD8 TILs displayed a distinctly heterogeneous exhaustion and activation status determined by differential 4-1BB expression levels, providing rationale and evidence for immunotherapies targeting co-stimulatory receptor 4-1BB in ovarian cancers.