Eradication of Established Tumors by CD8+ T Cell Adoptive Immunotherapy

Hanson, Holly L.; Donermeyer, David L.; Ikeda, Hiroaki; White, Janicé; Shankaran, Vijay; Old, Lloyd J.; Shiku, Hiroshi; Schreiber, Robert D.; Allen, Paul M.

doi:10.1016/s1074-7613(00)00026-1

Cited by 328 publications

(303 citation statements)

References 43 publications

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“…Investigations of transgenic mice with deficient responses to interferon-γ (IFN-γ), a cytokine that has been shown to be required for migration of T cells to tumour sites 58,59 , have led to increased interest in the mechanisms by which immune cells target tumours 60,61 . Although T cells seem to be the main effectors of immune surveillance 62 , the innate immune system (which includes natural killer cells, macrophages, monocytes and mast cells) is also involved [63][64][65] .…”

Section: Immune Function In the Tumour Contextmentioning

confidence: 99%

Putting tumours in context

2001

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The interactions between cancer cells and their micro-and macroenvironment create a context that promotes tumour growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets.Under normal conditions, ORGANS are made up of TISSUES that exchange information with other cell types via cell-cell contact, cytokines and the EXTRACELLULAR MATRIX (ECM). The ECM, which is produced by collaboration between STROMAL fibroblasts and EPITHELIAL cells, provides structural scaffolding for cells, as well as contextual information. The endothelial vasculature provides nutrients and oxygen, and cells of the immune system combat pathogens and remove apoptotic cells. Epithelial cells associate into intact, polarized sheets. These tissues communicate through a complex network of interactions: physically, through direct contact or through the intervening ECM, and biochemically, through both soluble and insoluble signalling molecules. In combination, these interactions provide the information that is necessary to maintain cellular differentiation and to create complex tissue structures.Occasionally, the intercellular signals that define the normal context become disrupted. Alterations in epithelial tissues can lead to movement of epithelial sheets and proliferationfor example, after activation of mesenchymal fibroblasts due to wounding. Normally, these conditions are temporary and reversible, but when inflammation is sustained, an escalating feedback loop ensues. Under persistent inflammatory conditions, continual upregulation of enzymes such as matrix metalloproteinases (MMPs) by stromal fibroblasts can disrupt the ECM, and invading immune cells can overproduce factors that promote abnormal proliferation.As this process progresses, the normal organization of the organ is replaced by a functional disorder (FIG. 1). If there are pre-existing epithelial cells within this changing context that possess tumorigenic potential, they can start to proliferate. Alternatively, the abnormal An innate anticancer mechanismAn important feature of the normal stromal context is the generation and maintenance of epithelial-cell polarity. Epithelial cells receive a variety of orientational cues from the environment that help them establish cellular apical and basal surfaces and to maintain the differentiated state. Loss of polarity has been shown to lead to increased cell proliferation and tumorigenesis (BOX 1). The basal surface of epithelial cells associates with the BASEMENT MEMBRANE, a specialized form of ECM that provides both structural support and polarization signals to epithelia. The basement membrane is a dynamic structure. Changes in its composition lead to changes in cell shape and behaviour 1 , altered binding affinity or cellular distribution of cell-surface receptors 2 , and cellu...

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Section: Immune Function In the Tumour Contextmentioning

confidence: 99%

Putting tumours in context

2001

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“…Starting with the pioneering work of Rammensee and colleagues [5,9], Kd has been widely studied, and Kd-specific immune responses described in a number of experimental systems. These include CD8 T cell responses: (1) against viral and bacterial pathogens [6,[19][20][21][22]; (2) in the NOD mouse model of diabetic autoimmunity [23][24][25][26][27]; and, (3), to tumor antigens [28][29][30][31]. Despite these many studies, the number of identified endogenously processed peptides selected by Kd is small.…”

Section: Introductionmentioning

confidence: 99%

Identification of naturally processed peptides bound to the class I MHC molecule H‐2K^d of normal and TAP‐deficient cells

et al. 2006

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This report details the biochemical features of natural peptides selected by the H-2K d class I MHC molecule. In normal cell lines, the length of the naturally processed peptides ranged from 8 to 18 amino acids, although the majority were 9-mers (16% were longer than nine residues). The binding motif for the 9-mer peptides was dominated by the presence of a tyrosine at P2 and an isoleucine/leucine at the P9 position. The P2 residue contributed most towards binding; and the short peptides bound better and formed longer-lived cell surface complexes than the long peptides, which bound poorly and dissociated rapidly. The longer peptides did not exhibit this strictly defined motif. Trimming the long peptides to their shorter forms did not enhance binding and conversely, extending the 9-mer peptides did not decrease binding. The long peptides were present on the cell-surface bound to H-2K d (Kd) and were not intermediate products of the class I MHC processing pathway. Finally, in two different TAP-deficient cells the long peptides were the dominant species, which suggested that TAPindependent pathways selected for long peptides by class I MHC molecules.

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“…Relatively slow induction of anti-HER2 immunoresponses after DNA vaccination may make the suppression of continuously growing tumors extremely difficult in the setting of these animal models. 30 Since one of the attractive characteristics of DNA vaccination is the long-lasting specific immune response to cognate antigens, DNA vaccination could be an attractive approach for preventing recurrence and metastasis of cancer, both of which often occur even after long latent periods. When the effect of DNA vaccination was investigated in pulmonary metastasis models of HER2-expressing tumors, we noted significant suppression of metastasis when immunization was initiated on the day of intravenous tumor challenge or 3 days after the tumor challenge.…”

Section: Discussionmentioning

confidence: 99%