Immune surveillance and tumour evasion

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The extraordinary features of the immune system make it possible to discern self from non-self. However, most human cancers, and pancreatic cancer in particular, are known to be poorly immunogenic, as crucial somatic genetic mutations can generate pancreatic cancer proteins that are essentially altered self proteins. Furthermore, promising immunotherapeutic approaches that have been used for relatively immunogenic cancers such as melanoma have met with variable success6. These observations have revealed that for tumours to form and progress, they must develop local and/or systemic mechanisms that subsequently allow them to escape the normal surveillance mechanisms of the intact immune system. Immune-based therapies must therefore incorporate at least one agent against a pancreatic cancer target as well as one or more agents that will modify both local and systemic mechanisms of pancreatic-cancer-induced IMMUNE TOLERANCE.

It is now clear that both local characteristics of the tumour microenvironment as well as systemic factors are important for the immune evasion of tumours. For example, T-cell recognition of pancreatic tumours might be inhibited or suppressed due to the downregulation of human leukocyte antigen (HLA) CLASS I tumour-antigen complexes on tumour cells by a range of intracellular mechanisms4, 7 — upregulation of immune-inhibition molecules11, 12, 13, 14, 15, 16, 17, loss of immune-regulation signals15, 16, 17, 18, 19, 20, 21, 22, 23 24, 25, 26, 27, 28, 29, 30, defects in immune-cell tumour localization31, 32, a3, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,

45, 46, 47, 48, 49, 50, 51 and loss of co-stimulatory molecules52, 53, 54, 55, 56, 57. Such alterations within a tumour cell would not be unexpected, as they have unstable genomes. The local inflammatory reaction is also an important triggering event in the recruitment of professional ANTIGEN-PRESENTING CELLS (APCs) and effector cells, such as T cells and NATURAL KILLER (NK) CELLS, to the tumour site. However, pancreatic tumour cells express a range of proteins that inhibit pro-inflammatory cytokines and DENDRITIC CELL (DC) MATURATION58, 59, 60.

In addition, the numbers of CD4+CD25+ T regulatory (TReg) CELLS — a subset of T cells that are known to be important in the suppression of self-reactive T cells (peripheral tolerance) — accumulate in pancreatic tumours61, 62, 63. Although these cells are thought to be activated during the immunization process, TReg cells seem to localize to tumour sites. Tumour production of the chemokine CCL22 probably attracts the TReg cells by interacting with the CCR4 receptor that is expressed by these cells64.

Other important elements in regulating the T-cell recognition of pancreatic tumours are the inhibitory pathways, known as 'immunological checkpoints'. Immunological checkpoints serve two purposes. One is to help generate and maintain self-tolerance, by eliminating T cells that are specific for self-antigens. The other is to restrain the amplitude of normal T-cell responses so that they do not 'overshoot' in their natural response to foreign pathogens. The prototypical immunological checkpoint is mediated by the cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) counter-regulatory receptor that is expressed by T cells when they become activated15, 23 CTLA4 binds two B7-FAMILY members on the surface APCs — B7.1 (also known as CD80) and B7.2 (also known as CD86) — with roughly 20-fold higher affinity than the T-cell surface protein CD28 binds these molecules. CD28 is a co-stimulatory receptor that is constitutively expressed on naive T cells. Because of its higher affinity, CTLA4 out-competes CD28 for B7.1/B7.2 binding, resulting in the downmodulation of T-cell responses20.

A range of B7-family members interact with co-stimulatory and counter-regulatory inhibitory receptors on T cells. Two recently discovered B7-family members, B7-H1 (also known as PD-L1) and B7-DC (also known as PD-L2) also seem to interact with T-cell co-stimulatory and counter-regulatory inhibitory receptors18, 29, 30. PD-L1, which is upregulated on T cells when they become activated, seems to control a counter-regulatory immunological checkpoint when it binds PD-1 26,28,29. Activating receptors for B7-DC and B7-H1 have not yet been definitively identified. B7-DC is expressed on DCs, and is likely to have a co-stimulatory role in increasing activation of naive or resting T cells. In contrast to B7.1, B7.2 and B7-DC, B7-H1 is also expressed on several peripheral tissues and on many tumours, including pancreatic tumours30.

Another new B7-family member, B7-H4, seems to mediate a predominantly inhibitory function in the immune system14. Recent data indicate that pancreatic tumours also express B7-H4 (D.L. and E.M.J., manuscript in preparation), and both B7-H1 and B7-H4 probably protect tumours from immune-system attack. Preclinical studies have already demonstrated that it is possible to downregulate B7-H1 signalling in mice, improving the antitumour response to vaccination18. Monoclonal antibodies that downregulate B7-H1 and B7-H4 are currently in clinical development. These antibodies will probably begin clinical testing in patients with pancreatic cancer within 2 to 3 years.

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Confident Kids

Confident Kids

Although nobody gets a parenting manual or bible in the delivery room, it is our duty as parents to try to make our kids as well rounded, happy and confident as possible. It is a lot easier to bring up great kids than it is to try and fix problems caused by bad parenting, when our kids have become adults. Our children are all individuals - they are not our property but people in their own right.

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