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CC BY 4.0 · Glob Med Genet 2022; 09(02): 097-109
DOI: 10.1055/s-0042-1743569
Original Article

CD24+ MDSC-DCs Induced by CCL5-Deficiency Showed Improved Antitumor Activity as Tumor Vaccines

Lei Huang
1   State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China
2   Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Zequn Ding
1   State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China
2   Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Yan Zhang
1   State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China
2   Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China
› Author Affiliations Funding This work was supported by funds from the National Natural Science Foundation of China (81773250 and 81972670 to Y.Z.).
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Abstract

Background Dendritic cell (DC) tumor vaccine has been extensively utilized in preclinical and clinical studies; however, this technique has encountered many difficulties, particularly in late-stage tumor patients. For those, ex vivo-induced DCs are actuallymyeloid-derived suppressive cells-derived DCs (MDSC-DCs). MDSCs with immunosuppressive activity, but not monocytes, became the major DC precursor. Thus, how to enhance antitumor activity of MDSC-DCs is urgent need to address.

Methods We utilized 4T1 and MC38 tumor-bearing both wildtype and CC chemokine ligand 5−/− (CCL5−/−) mice as animal models. MDSC-DCs were induced from splenocytes of these mice by granulocyte macrophage–colony stimulating factor/interleukin-4 with or without all-trans-retinoic acid (ATRA) in vitro for 7 days, then incubated with tumor-cell-lysis to treat mouse models for total three doses. For human MDSC-DCs, peripheral bloods from colorectal cancer patients were induced in vitro as murine cells with or without T- lymphocytes depletion to get rid of CCL5.

Results Flow cytometry analysis showed that MDSCs from CCL5 −/− mice could be induced into a new type of CD24+ MDSC-DCs in the presence of ATRA, which had more antitumor activity than control. Antibody blocking and adoptive transfer experiments demonstrated that downregulation of regulatory T cells (Tregs) mediated the inhibition of CD24+ MDSC-DCs on tumor growth. Mechanically, CD24+ MDSC-DCs inhibited Tregs' polarization by secreting cytokine or coactivators' expression. What's important, decreasing CCL5 protein levels by T- lymphocytes depletion during both murine and human MDSC-DCs in vitro induction could also acquire CD24+ MDSC-DCs.

Conclusion Knockdown of CCL5 protein during MDSC-DCs culture might provide a promising method to acquire DC-based tumor vaccines with high antitumor activity.

Keywords

CD24+ MDSC-DCs - CCL5-deficiency - tumor vaccines - antitumor activity - Tregs

Authors' Contributions

Y.Z. and L.H. were involved in conception and design and development of methodology. L.H., ZQ.Z., and Y.Z. helped in acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.). L.H., ZQ.D., W.-Q.G., and Y.Z. contributed substantially in analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis). L.H., ZQ.D., W.-Q.G., and Y.Z. were involved in writing, review, and/or revision of the manuscript. Y.Z. was involved in administrative, technical, or material support. W.-Q. G. and Y.Z. supervised the study.


Supplementary Material



Publication History

Received: 22 December 2021

Accepted: 21 January 2022

Article published online:
08 March 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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