Restifo, N.P., Dudley, M.E. & Rosenberg, S.A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269-281

Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature Reviews Immunology (Impact Factor: 34.99). 03/2012; 12(4):269-81. DOI: 10.1038/nri3191
Source: PubMed


Immunotherapy based on the adoptive transfer of naturally occurring or gene-engineered T cells can mediate tumour regression in patients with metastatic cancer. Here, we discuss progress in the use of adoptively transferred T cells, focusing on how they can mediate tumour cell eradication. Recent advances include more accurate targeting of antigens expressed by tumours and the associated vasculature, and the successful use of gene engineering to re-target T cells before their transfer into the patient. We also describe how new research has helped to identify the particular T cell subsets that can most effectively promote tumour eradication.

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    • "Because the specific MDSC subpopulations required for T cell suppression remains controversial, efforts to engineer MDSCs have not yet advanced to the point at which a defined cell type is used therapeutically (Highfill et al., 2010; Yin et al., 2010). Similarly, inhibiting the key suppressive subtype(s) of MDSCs to enhance T cell function might be an avenue to improve antitumor immunity via interruption of the tumor-induced immunosuppressive milieu (Gajewski et al., 2013; McAllister and Weinberg, 2014; Restifo et al., 2012). "
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    ABSTRACT: Nonresolving inflammation expands a heterogeneous population of myeloid suppressor cells capable of inhibiting T cell function. This heterogeneity has confounded the functional dissection of individual myeloid subpopulations and presents an obstacle for antitumor immunity and immunotherapy. Using genetic manipulation of cell death pathways, we found the monocytic suppressor-cell subset, but not the granulocytic subset, requires continuous c-FLIP expression to prevent caspase-8-dependent, RIPK3-independent cell death. Development of the granulocyte subset requires MCL-1-mediated control of the intrinsic mitochondrial death pathway. Monocytic suppressors tolerate the absence of MCL-1 provided cytokines increase expression of the MCL-1-related protein A1. Monocytic suppressors mediate T cell suppression, whereas their granulocytic counterparts lack suppressive function. The loss of the granulocytic subset via conditional MCL-1 deletion did not alter tumor incidence implicating the monocytic compartment as the functionally immunosuppressive subset in vivo. Thus, death pathway modulation defines the development, survival, and function of myeloid suppressor cells. Copyright © 2014 Elsevier Inc. All rights reserved.
    Full-text · Article · Dec 2014 · Immunity
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    • "A sequence relationships between the known human MHC class I protein and any vaccinia virus proteins was not found in the list of identified sequence relationships. Otherwise, our search results showed that T cell receptors associated with activation of the anti-cancer response and five vaccinia virus proteins had a sequence relationship to MHC class Ⅱ molecules involved with the T cell receptors [8]. As mentioned above, manipulating a viral vector to remove negatively affected genes, attach positively affected genes, or the use of engineered viral genes could yield effective results in cancer immunology therapy [15] [16]. "
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    ABSTRACT: The use of vaccinia virus, an oncolytic virus, in cancer immune therapy enhances the overall immune response. The mechanism of immune response against cancer and virus infection is similar. We found sequence relationships between vaccinia virus proteins and human proteins that are often regarded as hallmarks of cancer. From comparing human and vaccinia virus protein sequences, genetically engineered viruses associated with immune response have been used for cancer immune therapy in many clinical trials. Using published papers about cancer immunology, we classified proteins as either positively or negatively associated with cancer immune therapy. We searched for sequence relationships between human proteins and vaccinia virus proteins that are related to the classified proteins.
    Full-text · Conference Paper · Nov 2014
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    • "Cancer vaccines were designed to activate certain immune cells to recognize one or more tumor-specific antigen and to attack cancer cells [27], which were challenged in two aspects: identifying more suitable antigens, and requiring efficient approaches to stimulate immune response, which was either through delivery synthetic compounds to mammalian cells, like peptide vaccines , DNA vaccines and viral vector-based vaccines, or through preloading tumor antigens to DC cells in vitro [27]. In contrast, ACT focused on primary T cell therapy, which could partially resolve the mechanisms of self-tolerance that impeded T cell activation in vivo [28] [29]. The effectiveness of ACT in CRC has been investigated in several studies and revealed some exciting results. "
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    ABSTRACT: Increasing evidence showed invariant NKT cells (iNKT cell) are an attractive candidate for cancer immunotherapy, but its role in colorectal cancer treatment was still unclear. Here we reported iNKT cells exerted moderate cytotoxic effect against colorectal cancer cells (CRC cells) with the stimulation of α-Galcer, and the mutual recognition between CRC and iNKT cells could be greatly enhanced by Thymosinα1 (TA), which resulted in stronger killing efficiency both in vitro and in vivo. TA is widely used as an immune adjuvant for cancer therapy, but how it works on cancer cells still remains unclear. We found TA could upregulate CD80, B7H2 and CD1d expression on CRC cells. However, neutralization assay revealed iNKT cells' activation depended on CD1d expression rather than CD80 or B7H2. Moreover, colon cancer stem cells expressed higher CD1d level, which accounted for their greater sensitization to iNKT cells. Mechanistically, inhibition of Erk/MAPK pathway greatly attenuated the upregulation of CD1d by TA. Taken together, depending on Erk/MAPK pathway, TA promoted the activation and cytotoxicity of iNKT cells via upregulating CD1d expression on CRC cells, which indicated a novel immunotherapeutic strategy of iNKT cells against CRC.
    Full-text · Article · Oct 2014 · Cancer Letters
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