TGF-β and tumors—an ill-fated alliance

Moutsopoulos, Niki M.; Wen, Jie; Wahl, Sharon M.

doi:10.1016/j.coi.2008.04.003

Cited by 54 publications

(43 citation statements)

References 49 publications

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“…Our findings provide a model for mechanistic dissection of alterations of the tumor surveillance mechanisms during the course of TB infection. In addition, they may suggest an earlier unrecognized mechanism of reactivation of latent TB infection-as keratinocytes and tumor cells are known to produce a battery of pro-inflammatory and immunosuppressive cytokines (Pastore et al, 2006;Moutsopoulos et al, 2008), those cells may substantially contribute to the breakdown of local immunity. This, yet mostly hypothetical, mechanism may, however, represent a novel facet of a general virulence strategy of MTB-the ability to persist in a face of active immunity and hijack host responses to modify the local microenvironment to the pathogen's benefit.…”

Section: Discussionmentioning

confidence: 99%

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

et al. 2009

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Coexistence of pulmonary tuberculosis (TB) and lung cancer in clinic poses significant challenges for the diagnostic and treatment of both diseases. Although association of chronic inflammation and cancer is welldocumented, causal relationship between TB infection and lung cancer are not understood. We present experimental evidence that chronic TB infection induces cell dysplasia and squamous cell carcinoma (SCC) in a lung-specific manner. First, squamous cell aggregates consistently appeared within the lung tissue associated with chronic TB lesions, and in some cases resembled SCCs. A transplantable tumor was established after the transfer of cells isolated from TB lung lesions into syngeneic recipients. Second, the (Mycobacterium tuberculosis) MTB-infected macrophages play a pivotal role in TBinduced carcinogenesis by inducing DNA damage in their vicinity and by the production of a potent epidermal growth factor epiregulin, which may serve as a paracrine survival and growth factor responsible for squamous metaplasia and tumorigenesis. Third, lung carcinogenesis during the course of chronic TB infection was more pronounced in animals with severe lung tissue damage mediated by TB-susceptibility locus sst1. Together, our experimental findings showed a causal link between pulmonary TB and lung tumorigenesis and established a genetic model for further analysis of carcinogenic mechanisms activated by TB infection.

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Section: Discussionmentioning

confidence: 99%

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

et al. 2009

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“…It has been suggested that anti-tumor efficacy is limited against late-stage tumor compared to early-stage tumor, because the inhibitory tumor environment blocked lymphocyte activation through secretion of inhibitory cytokines, such as TGF-β and IL-10. 40,41 To solve the problem, reduction of tumor-burden in the host before adoptive transfer immunotherapy may provide an alternative way to improve therapeutic efficacy. 19,37 In our study, we did deplete Treg from TILs, however, the results may be further improved if we extend our strategy to select antigenspecific lymphocytes and expand them in vitro before adoptive cell transfer.…”

Section: Resultsmentioning

confidence: 99%

Depletion of CD4+CD25high regulatory T cells from tumor infiltrating lymphocytes predominantly induces Th1 type immune response in vivo which inhibits tumor growth in adoptive immunotherapy

Xu¹,

Wang²,

Jiang³

et al. 2009

Cancer Biology & Therapy

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“…The latter also mediates Treg-induced inhibition of effector T-cell reactivity 10 or directly targets effector T cells. 11 Thus, we hypothesized that targeting Cbl-b as an important regulator of TGF-b sensitivity in adoptively transferred polyclonal effector T cells, might serve as an innovative approach to induce resistance of ATC to these suppressive milieu effects.…”

Section: Cancer Immunotherapy By Engineered Cd8+ T Cells and DCmentioning

confidence: 99%

Reinforcement of cancer immunotherapy by adoptive transfer of cblb‐deficient CD8⁺ T cells combined with a DC vaccine

et al. 2011

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The success of cancer immunotherapy is limited by potent endogenous immune-evasion mechanisms, which are at least in part mediated by transforming growth factor-b (TGF-b). The E3 ubiquitin ligase Cbl-b is a key regulator of T cell activation and is established to regulate TGF-b sensitivity. cblb-deficient animals reject tumors via CD8 + T cells, which make Cbl-b an ideal target for improvement of adoptive T-cell transfer (ATC) therapy. In this study, we show that cblb-deficient CD8 + T cells are hyper-responsive to T-cell receptor (TCR)/CD28-stimulation and are in part protected against the negative cues induced by TGF-b in vitro. Notably, adoptive transfer of polyclonal, non-TCR transgenic cblb-deficient CD8 + T cells is not sufficient to reject B16-ova or EG7 tumors in vivo. Thus, cblb-deficient ATC requires proper in vivo re-activation by a dendritic cell (DC) vaccine. In strict contrast to ATC monotherapy, this approach delayed tumor outgrowth and significantly increased survival rates, which is paralleled by increased CD8 + T-cells infiltration to the tumor site and enrichment of ova-specific and interferon-c (IFN-c)-secreting CD8 + T cell in the draining lymph node (LN). Moreover, CD8 + T cells from cblb-deficient mice vaccinated with the DC vaccine show increased cytolytic activity in vivo. In summary, our data using cblb-deficient polyclonal, non-TCR-transgenic adoptively transferred CD8 + T cells into immuno-competent non-lymphodepleted recipients suggest that targeting Cbl-b might serve as a novel 'adjuvant approach', suitable to augment the effectiveness of established anti-cancer immunotherapies.

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TGF-β and tumors—an ill-fated alliance

Cited by 54 publications

References 49 publications

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

Depletion of CD4+CD25high regulatory T cells from tumor infiltrating lymphocytes predominantly induces Th1 type immune response in vivo which inhibits tumor growth in adoptive immunotherapy

Reinforcement of cancer immunotherapy by adoptive transfer of cblb‐deficient CD8⁺ T cells combined with a DC vaccine

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TGF-β and tumors—an ill-fated alliance

Cited by 54 publications

References 49 publications

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

Depletion of CD4+CD25high regulatory T cells from tumor infiltrating lymphocytes predominantly induces Th1 type immune response in vivo which inhibits tumor growth in adoptive immunotherapy

Reinforcement of cancer immunotherapy by adoptive transfer of cblb‐deficient CD8+ T cells combined with a DC vaccine

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Reinforcement of cancer immunotherapy by adoptive transfer of cblb‐deficient CD8⁺ T cells combined with a DC vaccine