Frontiers in Immunology | 卷:10 |
L-Selectin Enhanced T Cells Improve the Efficacy of Cancer Immunotherapy | |
Miriam Vigar1  Ruban R. P. Durairaj1  H. Angharad Watson1  Rebar N. Mohammed1  Markella Alatsatianos1  Julia Ohme1  Sophie G. Reed1  Christopher Marshall2  Stephen J. Paisey2  Hanan Almutairi2  Ann Ager3  Awen Gallimore3  | |
[1] Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom; | |
[2] PET Imaging Centre, School of Medicine, Cardiff University, Cardiff, United Kingdom; | |
[3] Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom; | |
关键词: L-selectin/CD62L; T cells; melanoma; adoptive T cell therapy; cancer immunotherapy; | |
DOI : 10.3389/fimmu.2019.01321 | |
来源: DOAJ |
【 摘 要 】
The homing molecule, L-selectin (CD62L), is commonly used as a T cell activation marker, since expression is downregulated following engagement of the T cell receptor. Studies in mice have shown that CD62L+ central memory T cells are better at controlling tumor growth than CD62L− effector memory T cells, while L-selectin knockout T cells are poor at controlling tumor growth. Here, we test the hypothesis that T cells expressing genetically modified forms of L-selectin that are maintained following T cell activation (L-selectin enhanced T cells) are better at controlling tumor growth than wild type T cells. Using mouse models of adoptive cell therapy, we show that L-selectin enhancement improves the efficacy of CD8+ T cells in controlling solid and disseminated tumor growth. L-selectin knockout T cells had no effect. Checkpoint blockade inhibitors synergized with wild type and L-selectin enhanced T cells but had no effect in the absence of T cell transfers. Reduced tumor growth by L-selectin enhanced T cells correlated with increased frequency of CD8+ tumor infiltrating T cells 21 days after commencing therapy. Longitudinal tracking of Zirconium-89 (89Zr) labeled T cells using PET-CT showed that transferred T cells localize to tumors within 1 h and accumulate over the following 7 days. L-selectin did not promote T cell homing to tumors within 18 h of transfer, however the early activation marker CD69 was upregulated on L-selectin positive but not L-selectin knockout T cells. L-selectin positive and L-selectin knockout T cells homed equally well to tumor-draining lymph nodes and spleens. CD69 expression was upregulated on both L-selectin positive and L-selectin knockout T cells but was significantly higher on L-selectin expressing T cells, particularly in the spleen. Clonal expansion of isolated L-selectin enhanced T cells was slower, and L-selectin was linked to expression of proliferation marker Ki67. Together these findings demonstrate that maintaining L-selectin expression on tumor-specific T cells offers an advantage in mouse models of cancer immunotherapy. The beneficial role of L-selectin is unrelated to its' well-known role in T cell homing and, instead, linked to activation of therapeutic T cells inside tumors. These findings suggest that L-selectin may benefit clinical applications in T cell selection for cancer therapy and for modifying CAR-T cells to broaden their clinical scope.
【 授权许可】
Unknown