Superior Antitumor Efficacy of IFN-α2b-Incorporated Photo-Cross-Linked Hydrogels Combined with T Cell Transfer and Low-Dose Irradiation Against Gastric Cancer.
Introduction
The exhaustion and poor homing of activated lymphocytes are critical obstacles in adoptive cell immunotherapy for solid tumors. In order to effectively deliver immune cells into tumors, we encapsulated interferon-α2b (IFN-α2b) into macroporous hydrogels as an enhancement factor and utilized low-dose irradiation (LDI) as a tumoral attractor of T cells.


Methods
Hydroxypropyl cellulose hydrogels were prepared by irradiation techniques, and the cross-sectional microstructure was characterized by scanning electron microscopy. The synergistic antitumor mechanism of combination of IFN-α2b and CIK cells was evaluated by detecting the expression of activation marker CD69 on CIK cell surface and IFN-γ production by CIK cells. The in vivo antitumor activity of IFN-α2b-incorporated hydroxypropyl cellulose hydrogels combined with CIK and radiation was evaluated in an MKN-45 xenografted nude mice model.


Results
The bioactivity of IFN-α2b was well maintained in ultraviolet-reactive, rapidly cross-linkable hydroxypropyl cellulose hydrogels. In vitro studies demonstrated IFN-α2b-activated T cells, as evidenced by upregulating early activation marker CD69 and secretion inflammatory cytokine IFN-γ. In vivo real-time image showed our hydrogels kept a higher amount of drug delivery at the tumor site for a long time compared with free drug injection. Low-dose irradiation promoted T cell accumulation and infiltration in subcutaneous tumors. Combination of IFN-α2b-loaded hydrogels (Gel-IFN) with T cells and LDI exhibited higher efficacy to eradicate human gastric cancer xenograted tumors with less proliferating cells and more necrotic regions compared with IFN-α2b or T cells alone.


Discussion
HPC hydrogels kept the activity of IFN-α2b and stably release of IFN-α2b to stimulate T cells for a long time. At the same time, low-dose radiation recruits T cells into tumors. This innovative integration mode of IFN-α2b-loaded hydrogels and radiotherapy offers a potent strategy to improve the therapeutic outcome of T cell therapy.
['Liu|Qin|Q|', 'Zhang|Dinghu|D|', 'Qian|Hanqing|H|0000-0002-7743-6019', 'Chu|Yanhong|Y|', 'Yang|Yan|Y|', 'Shao|Jie|J|', 'Xu|Qiuping|Q|', 'Liu|Baorui|B|']
D000818:Animals D000970:Antineoplastic Agents D045744:Cell Line, Tumor D049109:Cell Proliferation D002482:Cellulose D003432:Cross-Linking Reagents D004307:Dose-Response Relationship, Radiation D004583:Electrons D006801:Humans D020100:Hydrogels D000077190:Interferon alpha-2 D016898:Interferon-alpha D008027:Light D008297:Male D008807:Mice, Inbred BALB C D008819:Mice, Nude D013274:Stomach Neoplasms D013601:T-Lymphocytes D023041:Xenograft Model Antitumor Assays
hydrogels low-dose irradiation gastric cancer interferon-α2b adoptive cell transfer