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. 2020 Sep 22;6(3):697-711.
doi: 10.1016/j.bioactmat.2020.09.002. eCollection 2021 Mar.

The construction of a lymphoma cell-based, DC-targeted vaccine, and its application in lymphoma prevention and cure

Tianlin Zhou  1 , Jinrong Peng  1 , Ying Hao  1 , Kun Shi  1 , Kai Zhou  1 , Yun Yang  1 , Chengli Yang  1 , Xinlong He  1 , Xinmian Chen  2 , Zhiyong Qian  1
Affiliations

The construction of a lymphoma cell-based, DC-targeted vaccine, and its application in lymphoma prevention and cure

Tianlin Zhou et al. Bioact Mater. .

Abstract

In recent years, Non-Hodgkin lymphoma (NHL) has been one of the most fast-growing malignant tumor diseases. NHL poses severe damages to physical health and a heavy burden to patients. Traditional therapies (chemotherapy or radiotherapy) bring some benefit to patients, but have severe adverse effects and do not prevent relapse. The relevance of emerging immunotherapy options (immune-checkpoint blockers or adoptive cellular methods) for NHL remains uncertain, and more intensive evaluations are needed. In this work, inspired by the idea of vaccination to promote an immune response to destroy tumors, we used a biomaterial-based strategy to improve a tumor cell-based vaccine and constructed a novel vaccine named Man-EG7/CH@CpG with antitumor properties. In this vaccine, natural tumor cells are used as a vector to load CpG-ODN, and following lethal irradiation, the formulations were decorated with mannose. The study of the characterization of the double-improved vaccine evidenced the enhanced ability of DCs targeting and improved immunocompetence, which displayed an antitumor function. In the lymphoma prevention model, the Man-EG7/CH@CpG vaccine restrained tumor formation with high efficiency. Furthermore, unlike the non-improved vaccine, the double-improved vaccine elicited an enhanced antitumor effect in the lymphoma treatment model. Next, to improve the moderate therapeutic effect of the mono-treatment method, we incorporated a chemotherapeutic drug (doxorubicin, DOX) into the process of vaccination and devised a combination regimen. Fortunately, a tumor inhibition rate of ~85% was achieved via the combination therapy, which could not be achieved by mono-chemotherapy or mono-immunotherapy. In summary, the strategy presented here may provide a novel direction in the establishment of a tumor vaccine and is the basis for a prioritization scheme of immuno-chemotherapy in enhancing the therapeutic effect on NHL.

Keywords: Combinational therapy; DCs targeting; Man-EG7/CH@CpG vaccine; Non-hodgkin lymphoma.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Scheme 1
Scheme 1
Schematic view of Man-EG7/CH@CpG vaccine combination with DOX drugs in lymphoma therapy.
Fig. 1
Fig. 1
Preparation of double-improved Man-EG7/CH@CpG vaccine. (A) Scheme of the construction of the Man-EG7/CH@CpG vaccine. (B) Gel-retarding assay of the chitosan/CpG complex. (C) Co-localized fluorescent images of tumor cell-based, CpG loaded, and mannose-binding formulation (scale bar, 100 μm). (D) Flow cytometry detection of co-localized efficiency of adjuvant uptake and targeting ligand decoration. The results are shown as mean ± SEM, ***P < 0.001 compared with the related control group by two-tailed Student's t-test.
Fig. 2
Fig. 2
Uptake characterization of vaccine via BMDCs. (A) Schematic view of the uptake of vaccine via DCs. (B) Fluorescence assay of uptake efficiency by BMDCs of double-improved vaccine (scale bar, 100 μm). (C) Flow cytometry detection of uptake efficiency of Man-EG7/CH@CpG by BMDCs. (D, E) Statistics of BMDCs' uptake efficiency of mono- or double-improved vaccine via flow cytometry detection. The results are shown as mean ± SEM, ***P < 0.001 compared to the related control group by two-tailed Student's t-test.
Fig. 3
Fig. 3
Man-EG7/CH@CpG vaccine efficiently activates BMDCs in vitro. (A) Mature situations of BMDCs in different stimulation conditions. (B) Statistics of mature efficiency after the different stimulations. (C) The mRNA expression of cytokine of tumor necrosis factor (TNFα) was detected by a qPCR assay. (D–F) The mRNA expression of interferons (IFNα4, IFNβ, and IFNγ) was detected by qPCR. The results are shown as mean ± SEM, *P < 0.5, **P < 0.01.
Fig. 4
Fig. 4
Double-improved Man-EG7/CH@CpG vaccine enhances APCs targeting efficiency in the lymph nodes. (A) Enhanced targeting effect of lymph node of tumor cell-based vaccine, which was decorated with DCs' targeting ligand. (B, C) Statistics of lymph node uptake efficiency and MFI, which was evaluated by flow cytometry at a separate time point. (D) The uptake situation of the vaccine at each time point by resident DCs was tested. (E) The uptake situation of the vaccine at each time point by resident macrophages was examined. *P < 0.5 compared to the related control group by two-tailed Student's t-test. For all experiments, the results are shown as mean ± SEM.
Fig. 5
Fig. 5
The Man-EG7/CH@CpG vaccine promotes endogenous T lymphocyte proliferation and effectively inhibits tumor formation in the lymphoma prevention model. (A) Schematic diagram of the vaccination protocol. (B) Representative images of tumor formation of the EG7 prevention model (n = 4 for each group). The dotted circles show the blank of tumor growth. (C) Tumor weight in different treatments for the prevention of EG7 lymphoma. (D) Representative images of lymph node of mice (n = 4 for each group, scale bars, 100 μm). (E) The proliferation of splenic lymphocytes of each group in vitro. *P < 0.5, **P < 0.01, compared to the related control group by two-tailed Student's t-test. Error bars represent SEM for n = 4.
Fig. 6
Fig. 6
The Man-EG7/CH@CpG vaccine induces a significant antitumor effect in the lymphoma treatment model. (A) Schematic diagram of the treatment of lymphoma in mice. (B) Tumor volume of whole groups versus time, and tumor volume was monitored every two days. (C) Tumor images of each treatment group (n = 4 for each group). (D) Tumor weight in different treatments in the transplantable EG7 lymphoma model (Student's t-test, **P < 0.01).
Fig. 7
Fig. 7
The combination of chemotherapeutic drug and Man-EG7/CH@CpG vaccine induced a synergetic antitumor effect in vivo. (A) Schematic diagram of the establishment of the lymphoma model and the administration of immune-chemotherapy. (B) Tumor images of each group harvested from animals after immuno-chemotherapy (n = 4 for each group, a white dashed circle means the absence of tumors). (C) Tumor volume of whole groups versus time monitored every two days. (D) Tumor weights of each group. (E) Tumor volume of individual groups versus time was monitored every two days. (F) Survival curve of different treatments in established tumors. The group of Man-EG7/CH@CpG vaccine and DOX drug exhibited an overall survival benefit. (n = 4, *P < 0.05, **P < 0.01, ***P < 0.001.).
Fig. 8
Fig. 8
Activation of antitumor immune response by Man-EG7/CH@CpG vaccine combination with a chemotherapeutic drug. (A) The fluorescent images of tumor infiltration lymphocytes (CD3+CD8+) in tumor tissues from different therapeutic EG7 lymphoma mice. (B) The number of spleen-derived suppressive immune cells (CD3+/CD4+/FOXP3+ T cells) and activated immune cells (CD3+/CD8+/IFNγ+ T cells) in the lymphoma treatment model. (C) The number of lymph node-derived suppressive immune cells (CD3+/CD4+/FOXP3+ T cells) and activated immune cells (CD3+/CD4+/IFNγ+ T cells) in the lymphoma treatment model. All experimental data were analyzed as mean ± SEM and *P < 0.05, **P < 0.01, ***P < 0.001 (Student's t-test).
Fig. 9
Fig. 9
Safety evaluation of Man-EG7/CH@CpG vaccine combination with a chemotherapeutic drug. (A) Representative HE staining images of organs harvested from animals in each treatment group (scale bar, 100 μm). (B) Weight changing curves of mice after different treatments (n = 4 for each group).
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