Abrogation of Src Homology Region 2 Domain-Containing Phosphatase 1 in Tumor-Specific T Cells Improves Efficacy of Adoptive Immunotherapy by Enhancing the Effector Function and Accumulation of Short-Lived Effector T Cells In Vivo
Ingunn M. StromnesCarla FowlerChanel C. CasaminaChristina M. GeorgopolosMegan S. McAfeeThomas M. SchmittXiaoxia TanTae‐Don KimInpyo ChoiJoseph N. BlattmanPhilip D. Greenberg
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T cell expression of inhibitory proteins can be a critical component for the regulation of immunopathology owing to self-reactivity or potentially exuberant responses to pathogens, but it may also limit T cell responses to some malignancies, particularly if the tumor Ag being targeted is a self-protein. We found that the abrogation of Src homology region 2 domain-containing phosphatase-1 (SHP-1) in tumor-reactive CD8(+) T cells improves the therapeutic outcome of adoptive immunotherapy in a mouse model of disseminated leukemia, with benefit observed in therapy employing transfer of CD8(+) T cells alone or in the context of also providing supplemental IL-2. SHP-1(-/-) and SHP-1(+/+) effector T cells were expanded in vitro for immunotherapy. Following transfer in vivo, the SHP-1(-/-) effector T cells exhibited enhanced short-term accumulation, followed by greater contraction, and they ultimately formed similar numbers of long-lived, functional memory cells. The increased therapeutic effectiveness of SHP-1(-/-) effector cells was also observed in recipients that expressed the tumor Ag as a self-antigen in the liver, without evidence of inducing autoimmune toxicity. SHP-1(-/-) effector CD8(+) T cells expressed higher levels of eomesodermin, which correlated with enhanced lysis of tumor cells. Furthermore, reduction of SHP-1 expression in tumor-reactive effector T cells by retroviral transduction with vectors that express SHP-1-specific small interfering RNA, a translatable strategy, also exhibited enhanced antitumor activity in vivo. These studies suggest that abrogating SHP-1 in effector T cells may improve the efficacy of tumor elimination by T cell therapy without affecting the ability of the effector cells to persist and provide a long-term response.Keywords:
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Study of T-cell traits that predict response to therapy is complicated by the challenge that brain tumor antigens are largely uncharacterized. In other solid tumors, adoptive cell therapy has been demonstrated to be a highly efficacious immunotherapeutic strategy. Our OBJECTIVE is to demonstrate that we have generated an adoptive cell therapy platform that leads to the expansion and persistence of tumor-specific T lymphocytes without the need for prior antigen identification. Instead, TCR Vβ expression can be used to both identify and enrich for the tumor-specific T cell population. We employ bone marrow-derived dendritic cells pulsed with tumor-derived RNA to ex vivo expand tumor-specific T lymphocytes (TTRNA-T cells). After adoptive transfer of TTRNA-T cells, we are able to isolate the tumor-reactive T cells using flowcytometry based TCR Vβ spectratyping. These T cells can then be reliably expand from splenocytes of previously immunized mice. Functionality assays demonstrate that TTRNA-T cells with TCR Vβ families predicted to have high affinity to tumors were responsible for anti-tumor immunity. Adoptive cellular therapy using T cells expressing TCR Vβ 6 and TCR Vβ 8.1, 8.2 against intracranial tumor led to cures in 60% of treated mice. We further identify that the in vivo expansion of TCR Vβ 6+ T cells is associated with long term survival. Failure of the persistence of these T cells is directly associated with tumor escape. In patients that received adoptive cell therapy using our platform, we observed selective relative expansion of specific TCR Vβ families post-vaccination. Our methods allow us to generate highly tumor-reactive T cell populations without the need for identifying tumor antigens. We are currently employing these analyses in clinical trials of adoptive cellular therapy targeting pediatric and adult gliomas under development at our center (FDA IND BB-14058).
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Horticultural crops suffer from bacterial, fungal, and oomycete pathogens. Effectors are one of the main weapons deployed by those pathogens, especially in the early stages of infection. Pathogens secrete effectors with diverse functions to avoid recognition by plants, inhibit or manipulate plant immunity, and induce programmed cell death. Most identified effectors are proteinaceous, such as the well-studied type-III secretion system effectors (T3SEs) in bacteria, RXLR and CRN (crinkling and necrosis) motif effectors in oomycetes, and LysM (lysin motifs) domain effectors in fungi. In addition, some non-proteinaceous effectors such as toxins and sRNA also play crucial roles in infection. To cope with effectors, plants have evolved specific mechanisms to recognize them and activate effector-triggered immunity (ETI). This review summarizes the functions and mechanisms of action of typical proteinaceous and non-proteinaceous effectors secreted by important horticultural crop pathogens. The defense responses of plant hosts are also briefly introduced. Moreover, potential application of effector biology in disease management and the breeding of resistant varieties is discussed.
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Adoptive cell transfer (ACT) of genetically engineered T cells expressing cancer-specific T-cell receptors (TCR) is a promising cancer treatment. Here, we investigate the in vivo functional activity and dynamics of the transferred cells by analyzing samples from 3 representative patients with melanoma enrolled in a clinical trial of ACT with TCR transgenic T cells targeted against the melanosomal antigen MART-1. The analyses included evaluating 19 secreted proteins from individual cells from phenotypically defined T-cell subpopulations, as well as the enumeration of T cells with TCR antigen specificity for 36 melanoma antigens. These analyses revealed the coordinated functional dynamics of the adoptively transferred, as well as endogenous, T cells, and the importance of highly functional T cells in dominating the antitumor immune response. This study highlights the need to develop approaches to maintaining antitumor T-cell functionality with the aim of increasing the long-term efficacy of TCR-engineered ACT immunotherapy.A longitudinal functional study of adoptively transferred TCR–engineered lymphocytes yielded revealing snapshots for understanding the changes of antitumor responses over time in ACT immunotherapy of patients with advanced melanoma.
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Abstract Microbial plant pathogens use secreted effector proteins for successful infection of their host. This evolved state is rather exceptional as most microbes do not cause disease in the vast majority of plant species. An important primary activity of effectors is to interfere with a range of plant immune processes to evade and suppress pathogen detection, or to block immune signalling and downstream responses. Furthermore, effectors can enhance disease susceptibility by altering cellular processes and modulating host transcription. For most of these activities, effectors specifically target plant proteins that are central in these processes. An advanced virulence strategy is the post‐translational modification by effectors of plant targets to change their activity or stability. The knowledge gathered on the molecular mechanisms underlying effector‐triggered susceptibility of plants provides great potential for novel approaches of resistance breeding. Key Concepts Pathogens secrete and/or translocate effector proteins to promote plant disease. Besides their primary role in promoting disease, effectors or effector‐modified plant proteins can be recognised by resistance proteins to activate an effector‐triggered immune response. Many effectors block pathogen‐associated molecular pattern (PAMP)‐triggered immunity and/or effector‐triggered immunity. Other effectors rewire signalling pathways and reprogramme the plant cell to promote pathogen growth. Certain effectors can affect the activity or function of host proteins by post‐translational modifications e.g. (de)phosphorylation or targeting for proteosomal degradation.
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Plant diseases caused by fungal pathogens are typically initiated by molecular interactions between ‘effector’ molecules released by a pathogen and receptor molecules on or within the plant host cell. In many cases these effector-receptor interactions directly determine host resistance or susceptibility. The search for fungal effector proteins is a developing area in fungal-plant pathology, with more than 165 distinct confirmed fungal effector proteins in the public domain. For a small number of these, novel effectors can be rapidly discovered across multiple fungal species through the identification of known effector homologues. However, many have no detectable homology by standard sequence-based search methods. This study employs a novel comparison method (RemEff) that is capable of identifying protein families with greater sensitivity than traditional homology-inference methods, leveraging a growing pool of confirmed fungal effector data to enable the prediction of novel fungal effector candidates by protein family association. Resources relating to the RemEff method and data used in this study are available from https://figshare.com/projects/Effector_protein_remote_homology/87965 .
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