Culturing CTLs under Hypoxic Conditions Enhances Their Cytolysis and Improves Their Anti-tumor Function

Cell Reports

Yael Gropper¹  Guy Shakhar¹  Tali Feferman¹  Tomer-Meir Salame²  Ziv Porat²  Tali Shalit³ 

[1] Department of Immunology, Weizmann Institute of Science, Rehovot, 76100, Israel;Life Science Core Facilities, Weizmann Institute of Science, Rehovot, 76100, Israel;The Mantoux Bioinformatics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, 76100, Israel;

关键词: immunometabolism;    immunotherapy;    cell migration;    imaging;    cytotoxic T cells;    melanoma;    cytotoxicity;    hypoxia;    granzyme-B;    perforin;   

DOI  :  10.1016/j.celrep.2017.08.071

来源: DOAJ

【 摘 要 】

Cytotoxic T lymphocytes (CTLs) used in immunotherapy are typically cultured under atmospheric O2 pressure but encounter hypoxic conditions inside tumors. Activating CTLs under hypoxic conditions has been shown to improve their cytotoxicity in vitro, but the mechanism employed and the implications for immunotherapy remain unknown. We activated and cultured OT-I CD8 T cells at either 1% or 20% O2. Hypoxic CTLs survived, as well as normoxic ones, in vitro but killed OVA-expressing B16 melanoma cells more efficiently. Hypoxic CTLs contained similar numbers of cytolytic granules and released them as efficiently but packaged more granzyme-B in each granule without producing more perforin. We imaged CTL distribution and motility inside B16-OVA tumors using confocal and intravital 2-photon microscopy and observed no obvious differences. However, mice treated with hypoxic CTLs exhibited better tumor regression and survived longer. Thus, hypoxic CTLs may perform better in tumor immunotherapy because of higher intrinsic cytotoxicity rather than improved migration inside tumors.

【 授权许可】

Unknown