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Functional Immune Cell-Derived Exosomes Engineered for the Trilogy of Radiotherapy Sensitization.

ABSTRACT: The limited efficacy of radiotherapy leads to radio-resistance and high rates of tumor recurrence and metastasis, which is caused by tumor hypoxia, rapid DNA damage repair, and especially the suppressive immune microenvironment of tumor. Lots of immune cell-derived exosomes can regulate antitumor immunity, but their application in enhancing radiotherapy is rarely studied. Herein, as a model of concept, M1 macrophage-derived exosomes (M1Exos) is engineered as effective radiotherapy sensitizers, realizing the trilogy of radiotherapy sensitization: 1) M1Exos is engineered to express catalases on the inside of membrane, which can effectively relieve tumor hypoxia, and enhance DNA damage. 2) The DNA damage repair inhibitor is loaded in M1Exos to effectively inhibit DNA damage repair. 3) M1Exos can polarize M2 macrophages into M1 phenotypes, and the anti-PD-L1 nanobody engineered on the outside of M1Exos can relieve the immunosuppression of T cells, both ultimately leading to the remodeling of the tumor suppressive microenvironment. The trilogy of radiotherapy sensitization achieves excellent antitumor efficacy, exhibiting the good utility of engineering immune cell-derived exosomes as radiotherapy sensitizers, inspiring the future efforts to explore different kinds of immune cell-derived exosomes for enhanced radiotherapy.

SUBMITTER: Ma X

PROVIDER: S-EPMC9376809 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Functional Immune Cell-Derived Exosomes Engineered for the Trilogy of Radiotherapy Sensitization.

Ma Xiaotu X Yao Meinan M Gao Yu Y Yue Yale Y Li Yao Y Zhang Tianjiao T Nie Guangjun G Zhao Xiao X Liang Xiaolong X

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20220617 23

The limited efficacy of radiotherapy leads to radio-resistance and high rates of tumor recurrence and metastasis, which is caused by tumor hypoxia, rapid DNA damage repair, and especially the suppressive immune microenvironment of tumor. Lots of immune cell-derived exosomes can regulate antitumor immunity, but their application in enhancing radiotherapy is rarely studied. Herein, as a model of concept, M1 macrophage-derived exosomes (M1Exos) is engineered as effective radiotherapy sensitizers, r ...[more]

PMID: 35715382

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Project description:Exosomes (exos) contain molecular cargo of therapeutic and diagnostic value for cancers and other inflammatory diseases, but their therapeutic potential for periodontitis (PD) remains unclear. Dendritic cells (DCs) are the directors of immune response and have been extensively used in immune therapy. We previously reported in a mouse model of PD that custom murine DC-derived exo subtypes could reprogram the immune response toward a bone-sparing or bone-loss phenotype, depending on immune profile. Further advancement of this technology requires the testing of human DC-based exos with human target cells. Our main objective in this study is to test the hypothesis that human monocyte-derived dendritic cell (MoDC)-derived exos constitute a well-tolerated and effective immune therapeutic approach to modulate human target DC and T cell immune responses in vitro. MoDC subtypes were generated with TGFb/IL-10 (regulatory (reg) MoDCs, CD86lowHLA-DRlowPDL1high), E. coli LPS (stimulatory (stim) MoDCs, CD86highHLA-DRhighPDL1low) and buffer (immature (i) MoDCs, CD86lowHLA-DRmedPDL1low). Exosomes were isolated from different MoDC subtypes and characterized. Once released from the secreting cell into the surrounding environment, exosomes protect their prepackaged molecular cargo and deliver it to bystander cells. This modulates the functions of these cells, depending on the cargo content. RegMoDCexos were internalized by recipient MoDCs and induced upregulation of PDL1 and downregulation of costimulatory molecules CD86, HLADR, and CD80, while stimMoDCexos had the opposite influence. RegMoDCexos induced CD25+Foxp3+ Tregs, which expressed CTLA4 and PD1 but not IL-17A. In contrast, T cells treated with stimMoDCexos induced IL-17A+ Th17 T cells, which were negative for immunoregulatory CTLA4 and PD1. T cells and DCs treated with iMoDCexos were immune 'neutral', equivalent to controls. In conclusion, human DC exos present an effective delivery system to modulate human DC and T cell immune responses in vitro. Thus, MoDC exos may present a viable immunotherapeutic agent for modulating immune response in the gingival tissue to inhibit bone loss in periodontal disease.

Project description:BACKGROUND:We have recently shown that radiotherapy may not only be a successful local and regional treatment but, when combined with MSCs, may also be a novel systemic cancer therapy. This study aimed to investigate the role of exosomes derived from irradiated MSCs in the delay of tumor growth and metastasis after treatment with MSC + radiotherapy (RT). METHODS:We have measured tumor growth and metastasis formation, of subcutaneous human melanoma A375 xenografts on NOD/SCID-gamma mice, and the response of tumors to treatment with radiotherapy (2 Gy), mesenchymal cells (MSC), mesenchymal cells plus radiotherapy, and without any treatment. Using proteomic analysis, we studied the cargo of the exosomes released by the MSC treated with 2 Gy, compared with the cargo of exosomes released by MSC without treatment. RESULTS:The tumor cell loss rates found after treatment with the combination of MSC and RT and for exclusive RT, were: 44.4% % and 12,1%, respectively. Concomitant and adjuvant use of RT and MSC, increased the mice surviving time 22,5% in this group, with regard to the group of mice treated with exclusive RT and in a 45,3% respect control group. Moreover, the number of metastatic foci found in the internal organs of the mice treated with MSC + RT was 60% less than the mice group treated with RT alone. We reasoned that the exosome secreted by the MSC, could be implicated in tumor growth delay and metastasis control after treatment. CONCLUSIONS:Our results show that exosomes derived form MSCs, combined with radiotherapy, are determinant in the enhancement of radiation effects observed in the control of metastatic spread of melanoma cells and suggest that exosome-derived factors could be involved in the bystander, and abscopal effects found after treatment of the tumors with RT plus MSC. Radiotherapy itself may not be systemic, although it might contribute to a systemic effect when used in combination with mesenchymal stem cells owing the ability of irradiated MSCs-derived exosomes to increase the control of tumor growth and metastasis.

Project description:The suppressive nature of immune cells in the tumor microenvironment plays a major role in regulating anti-tumor immune responses. Our previous work demonstrated that a soluble factor from tumor cells is able to induce a suppressor phenotype (SP) in human CD8+ T cells typified by loss of CD27/CD28 expression and acquisition of a potent suppressor function. The present study hypothesized that the soluble mechanism that is inducing the SP in CD8+ T cells are tumor-derived exosomes (TDEs).Membrane vesicles and TDEs from multiple head and neck cancer cell line's conditioned growth media were isolated by ultracentrifugation and precipitation, respectively. Human purified CD3+CD8+ T cells were assessed for their induction of the T cell SP by flow cytometry identifying loss of CD27/CD28 expression and in vitro suppression assays. Furthermore, the T cell SP was characterized for the attenuation of IFN-γ production. To delineate exosomal proteins contributing to T cell SP, mass spectrometry was used to identify unique proteins that were present in TDEs. CRISPR/Cas9 knockout constructs were used to examine the role of one of these proteins, galectin-1. To assess the role of exosomal RNA, RNA purified from TDEs was nucleofected into CD8+ T cells followed by suppression analysis.Using fractionated conditioned growth media, factors >200 kDa induced CD8+ T cell SP, which was determined to be an exosome by mass spectrometry analysis. Multiple head and neck cancer-derived cell lines were found to secrete T cell SP-inducing exosomes. Mass spectrometry analysis revealed that an immunoregulatory protein, galectin-1 (Gal-1), was expressed in those exosomes, but not in TDEs unable to induce T cell SP. Galectin-1 knockout cells were found to be less able to induce T cell SP. Furthermore, RNA purified from the T cell SP-inducing exosomes were found to partially induce the SP when transfected into normal CD8+ T cells.For the first-time, TDEs have been identified to induce a SP in CD8+ T cells and their mode of action may be synergistic effects from exosomal proteins and RNA. One protein in particular, galectin-1, appears to play a significant role in inducing T cell SP. Therefore, tumor-derived immunosuppressive exosomes are a potential therapeutic target to prevent T cell dysfunction and enhance anti-tumor immune responses.

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Functional Immune Cell-Derived Exosomes Engineered for the Trilogy of Radiotherapy Sensitization.

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Functional Immune Cell-Derived Exosomes Engineered for the Trilogy of Radiotherapy Sensitization.

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