Interferon-γ and Tumor Necrosis Factor-α Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype

Jin, Ping; Zhao, Yuanlong; Liu, Hui; Chen, Jinguo; Ren, Jiaqiang; Jin, Jianjian; Bedognetti, Davide; Liu, Shutong; Wang, Ena; Marincola, Francesco M.; Stroncek, David F.

doi:10.1038/srep26345

Cited by 69 publications

(69 citation statements)

References 27 publications

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“…Immunostimulatory cytokines produced by TGF‐β CAR‐T cells may also directly contribute to reducing tumor cell numbers, as TNF‐α and IFN‐γ have been associated with restricted tumor cell growth . Importantly, in the in vivo tumor microenvironment, which includes other cell types absent from our experiments, immunostimulatory cytokines may recruit additional anti‐tumor mechanisms such as the polarization of macrophages and stromal cells toward proinflammatory phenotypes . Therefore, the anti‐tumor contribution of TGF‐β CAR‐T cells may be further enhanced in the more complex in vivo milieu.…”

Section: Discussionmentioning

confidence: 64%

TGF‐β–responsive CAR‐T cells promote anti‐tumor immune function

Hou

Chang

Lorenzini

et al. 2018

Bioengineering & Transla Med

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A chimeric antigen receptor (CAR) that responds to transforming growth factor beta (TGF‐β) enables the engineering of T cells that convert this immunosuppressive cytokine into a potent T‐cell stimulant. However, clinical translation of TGF‐β CAR‐T cells for cancer therapy requires the ability to productively combine TGF‐β responsiveness with tumor‐targeting specificity. Furthermore, the potential concern that contaminating, TGF‐β?producing regulatory T (Treg) cells may preferentially expand during TGF‐β CAR‐T cell manufacturing and suppress effector T (Teff) cells demands careful evaluation. Here, we demonstrate that TGF‐β CAR‐T cells significantly improve the anti‐tumor efficacy of neighboring cytotoxic T cells. Furthermore, the introduction of TGF‐β CARs into mixed T‐cell populations does not result in the preferential expansion of Treg cells, nor do TGF‐β CAR‐Treg cells cause CAR‐mediated suppression of Teff cells. These results support the utility of incorporating TGF‐β CARs in the development of adoptive T‐cell therapy for cancer.

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Section: Discussionmentioning

confidence: 64%

TGF‐β–responsive CAR‐T cells promote anti‐tumor immune function

Hou

Chang

Lorenzini

et al. 2018

Bioengineering & Transla Med

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“…This result indicated that MIC3 was an effective inducer of TNF-α. During acute infection with T. gondii , TNF-α acts synergistically with IFN-γ, resulting in the elimination of intracellular pathogens35. However, MIC3 did not induce any IFN-γ secretion compared with OVA in splenocytes (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 96%

Identification of a TNF-α inducer MIC3 originating from the microneme of non-cystogenic, virulent Toxoplasma gondii

Qiu

Wang

Zhang

et al. 2016

Sci Rep

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Toxoplasma gondii is an opportunistic parasite with avirulent cystogenic and highly virulent non-cystogenic isolates. Although non-cystogenic strains are considered the most virulent, there are also marked genetic and virulence differences among these strains. Excretory-secretory antigens (ESAs) of T. gondii are critical for the invasion process and the immune response of the host. To better understand the differences in virulence between non-cystogenic T. gondii isolates, we studied ESAs of the RH strain (Type I), and the very prevalent in China, but less virulent TgCtwh3 strain (Chinese 1). ESAs of RH and TgCtwh3 triggered different levels of TNF-α production and macrophage M1 polarization. Using iTRAQ analysis, 27 differentially expressed proteins originating from secretory organelles and surface were quantified. Of these proteins, 11 microneme-associated proteins (MICs), 6 rhoptry proteins, 2 dense granule proteins and 5 surface proteins were more abundant in RH than in TgCtwh3. The protein-protein correlation network was employed to identify the important functional node protein MIC3, which was upregulated 5-fold in RH compared with TgCtwh3. MIC3 was experimentally confirmed to evoke a TNF-α secretory response, and it also induced macrophage M1 polarization. This result suggests that MIC3 is a potentially useful immunomodulator that induces TNF-α secretion and macrophage M1 polarization.

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“…ELISA assay results indicated that the levels of IFN-γ and TNF-α were significantly increased in MUC1-CRT-infected BMDCs when compared with MUC1-infected BMDCs. Previous results have indicated that IFN-γ and TNF-α are essential immune effectors released by activated immunocytes (32,33,47). Therefore, the supernatant concentration of IFN-γ and TNF-α may indirectly represent the active extent of the immune system in vivo.…”

Section: Discussionmentioning

confidence: 99%

Calreticulin is an effective immunologic adjuvant to tumor-associated antigens

Wang

Gao

Qin

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. As a key molecule involved in cell recognition, calreticulin (CRT) may be expressed on the surface of (pre-) apoptotic cells and provide the signal that is recognized by dendritic cells (DCs) or other antigen presenting cells (APCs), which results in phagocytosis. Within the APCs, tumor-associated antigens (TAAs) may be subsequently presented to T lymphocytes, which triggers a specific antitumor immune response. It has been hypothesized that CRT is able to act as the immunologic adjuvant and translocate itself and TAAs to the cell surface and induce a specific antitumor immune response. In the present study, CRT was demonstrated to translocate itself and mucin 1 (MUC1), a breast cancer antigen, to the surface of 4T1 cells and the MUC1-CRT-coated cells were able to induce apoptosis in a time-dependent manner. When DCs were infected with adenovirus containing MUC1-CRT, an increase in T cell proliferation and cytokine production was exhibited. These results suggest that CRT may act as an immunologic adjuvant with MUC1 and induce a strong immune response.

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Interferon-γ and Tumor Necrosis Factor-α Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype

Cited by 69 publications

References 27 publications

TGF‐β–responsive CAR‐T cells promote anti‐tumor immune function

TGF‐β–responsive CAR‐T cells promote anti‐tumor immune function

Identification of a TNF-α inducer MIC3 originating from the microneme of non-cystogenic, virulent Toxoplasma gondii

Calreticulin is an effective immunologic adjuvant to tumor-associated antigens

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