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MRNA-engineered mesenchymal stromal cells expressing CXCR2 enhances cell migration and improves recovery in IBD.

ABSTRACT: Mesenchymal stromal cells (MSCs) have shown significant heterogeneity in terms of therapeutic efficacy for inflammatory bowel disease (IBD) treatment, which may be due to an insufficient number of MSCs homing to the damaged tissue of the colon. Engineering MSCs with specific chemokine receptors can enhance the homing ability by lentiviral transduction. However, the unclear specific chemokine profile related to IBD and the safety concerns of viral-based gene delivery limit its application. Thus, a new strategy to modify MSCs to express specific chemokine receptors using mRNA engineering is developed to evaluate the homing ability of MSCs and its therapeutic effects for IBD. We found that CXCL2 and CXCL5 were highly expressed in the inflammatory colon, while MSCs minimally expressed the corresponding receptor CXCR2. Transient expression of CXCR2 in MSC was constructed and exhibited significantly enhanced migration to the inflamed colons, leading to a robust anti-inflammatory effect and high efficacy. Furthermore, the high expression of semaphorins7A on MSCs were found to induce the macrophages to produce IL-10, which may play a critical therapeutic role. This study demonstrated that the specific chemokine receptor CXCR2 mRNA-engineered MSCs not only improves the therapeutic efficacy of IBD but also provides an efficient and safe MSC modification strategy.

SUBMITTER: Li Q

PROVIDER: S-EPMC8413681 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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mRNA-engineered mesenchymal stromal cells expressing CXCR2 enhances cell migration and improves recovery in IBD.

Li Qiaojia Q Lian Yufan Y Deng Yiwen Y Chen Jieying J Wu Tao T Lai Xinqiang X Zheng Bowen B Qiu Chen C Peng Yanwen Y Li Weiqiang W Xiang Andy Peng AP Zhang Xiaoran X Ren Jie J

Molecular therapy. Nucleic acids 20210721

Mesenchymal stromal cells (MSCs) have shown significant heterogeneity in terms of therapeutic efficacy for inflammatory bowel disease (IBD) treatment, which may be due to an insufficient number of MSCs homing to the damaged tissue of the colon. Engineering MSCs with specific chemokine receptors can enhance the homing ability by lentiviral transduction. However, the unclear specific chemokine profile related to IBD and the safety concerns of viral-based gene delivery limit its application. Thus, ...[more]

PMID: 34513306

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Project description:BackgroundAdoptive natural killer (NK) cell transfer is being increasingly used as cancer treatment. However, clinical responses have so far been limited to patients with hematological malignancies. A potential limiting factor in patients with solid tumors is defective homing of the infused NK cells to the tumor site. Chemokines regulate the migration of leukocytes expressing corresponding chemokine receptors. Various solid tumors, including renal cell carcinoma (RCC), readily secrete ligands for the chemokine receptor CXCR2. We hypothesize that infusion of NK cells expressing high levels of the CXCR2 chemokine receptor will result in increased influx of the transferred NK cells into tumors, and improved clinical outcome in patients with cancer.MethodsBlood and tumor biopsies from 14 primary RCC patients were assessed by flow cytometry and chemokine analysis. Primary NK cells were transduced with human CXCR2 using a retroviral system. CXCR2 receptor functionality was determined by Calcium flux and NK cell migration was evaluated in transwell assays.ResultsWe detected higher concentrations of CXCR2 ligands in tumors compared with plasma of RCC patients. In addition, CXCL5 levels correlated with the intratumoral infiltration of CXCR2-positive NK cells. However, tumor-infiltrating NK cells from RCC patients expressed lower CXCR2 compared with peripheral blood NK cells. Moreover, healthy donor NK cells rapidly lost their CXCR2 expression upon in vitro culture and expansion. Genetic modification of human primary NK cells to re-express CXCR2 improved their ability to specifically migrate along a chemokine gradient of recombinant CXCR2 ligands or RCC tumor supernatants compared with controls. The enhanced trafficking resulted in increased killing of target cells. In addition, while their functionality remained unchanged compared with control NK cells, CXCR2-transduced NK cells obtained increased adhesion properties and formed more conjugates with target cells.ConclusionsTo increase the success of NK cell-based therapies of solid tumors, it is of great importance to promote their homing to the tumor site. In this study, we show that stable engineering of human primary NK cells to express a chemokine receptor thereby enhancing their migration is a promising strategy to improve anti-tumor responses following adoptive transfer of NK cells.

Project description:BackgroundBispecific T-cell engagers (BiTEs) are recombinant bispecific proteins designed to stimulate polyclonal T-cell immunity. In recent years, B7H3, a pan-cancer antigen, has been considered a promising target for future immunotherapy. However, the B7H3-targeting BiTE faces the challenge of systemic toxicity. Oncolytic viruses (OVs) represent a new class of cancer immunotherapeutics and serve as an appropriate platform for locoregional delivery of therapeutic genes. In this study, we designed an oncolytic adenovirus (OAd) encoding BiTE targeting human B7H3. We hypothesized that OVs encoding B7H3 BiTE deliver this molecule persistently to the tumor site while mediating polyclonal T-cell activation and redirecting it to tumor cells.MethodsB7H3-targeting BiTE was constructed by linking a single-chain variable fragment (scFv) that recognizes human B7H3 to an scFv that recognizes human CD3. B7H3 BiTE was inserted into OAd to construct OAd-B7H3-BiTE. The function of the OV-delivered B7H3 BiTE was detected via co-culturing B7H3+ target cells and peripheral blood mononuclear cells. A humanized immune system mouse model was used to evaluate the therapeutic effects in vivo.ResultsB7H3 is highly expressed in a high proportion of human malignancies. OV-delivered BiTEs bind to T cells and target cells. We observed a series of phenomena reflecting T-cell activation induced by OAd-B7H3-BiTE, including cell clustering, cell size, activation markers, cytokine secretion, and proliferation. Furthermore, T-cell activation was mirrored by the corresponding cytotoxicity against B7H3+ tumor cells. In vivo, B7H3 BiTE was persistently expressed in tumors and enhanced the antitumor T-cell immune response.ConclusionsUsing an OV for the local expression of B7H3 BiTE maximizes the local concentration of BiTE while reducing systemic exposure. OV also provides a relatively "hot" T-cell immune environment for the function of BiTE. Because of its capacity to activate polyclonal T cells, BiTE has the potential to redirect virus-specific T cells to tumors. Our study provides new opportunities for the exploitation of B7H3-BiTE-armed OVs as therapeutic agents for the treatment of B7H3-positive malignancies.

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MRNA-engineered mesenchymal stromal cells expressing CXCR2 enhances cell migration and improves recovery in IBD.

Publications

mRNA-engineered mesenchymal stromal cells expressing CXCR2 enhances cell migration and improves recovery in IBD.

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