CompOnco Immune cancer

Tuesday, 23/03/2010  |   Cervical Cancer, Others  |  no comments

More than 500 million years ago a set of specialised enzymes and proteins evolved to defend our primitive ancestors against assaults from the outside world. If a microbe breached the shell of some Cambrian-era fauna, the members of this early-vintage immune system would stage a savage but coordinated attack on these interlopers¿punching holes in cell walls, spitting out chemical toxins, or simply swallowing and digesting the enemy whole. Once the invaders were dispatched, the immune battalion would start to heal damaged cells, or if the attacked cells were too badly damaged it would put them to rest. This inflammatory immune response worked so well that many aspects of it have been preserved during the protracted aeons of evolution. We know this to be true because studies have found that we share many of the same immune genes as the lowly fruit fly–and vertebrates and invertebrates diverged from a common ancestor in excess of half a billion years ago (Stix 2007). The concept that the immune system recognises and controls cancer was first postulated over a century ago, and cancer immunity has continued to be vigorously debated and experimentally tested. Mounting evidence in humans and mice supports the involvement of cytokines in tumour initiation, growth, and metastasis. The idea that the immune system detects stressed, transformed, and frankly malignant cells underpins much of the excitement currently surrounding new cytokine therapies in cancer treatment. In this review, we define the contrasting roles that cytokines play in promoting tumour immunity, inflammation, and carcinogenesis. We also discuss the more promising aspects of clinical cytokine use in cancer patients (Smyth et al 2004). Another important role of the immune system is to identify and eliminate tumours. The transformed cells of tumours express antigens that are not found on normal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumour cells. The antigens expressed by tumours have several sources;(Andersen et al 2006) some are derived from oncogenic viruses like human papillomavirus, which causes cervical cancer,(Boon et al 1996) while others are the organism’s own proteins that occur at low levels in normal cells but reach high levels in tumour cells. One example is an enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells (e.g. melanocytes) into tumours called melanomas. A third possible source of tumour antigens are proteins normally important for regulating cell growth and survival, that commonly mutate into cancer inducing molecules called oncogenes (Andersen et al 2006; Guevara-Patino et al 2003). It has been established that cancer can be promoted and/or exacerbated by inflammation and infections. Indeed, chronic inflammation orchestrates a tumour-supporting microenvironment that is an indispensable participant in the neoplastic process. The mechanisms that link infection, innate immunity, inflammation, and cancer are being unraveled at a fast pace. Important components in this linkage are the cytokines produced by activated innate immune cells that stimulate tumour growth and progression. In addition, soluble mediators produced by cancer cells recruit and activate inflammatory cells, which further stimulate tumour progression. However, inflammatory cells also produce cytokines that can limit tumour growth (Lin & Karin M 2007). The main response of the immune system to tumours is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells (Gerloni & Zanetti 2005). While most of the focus in cancer immunology is on CD8+ cytotoxic T lymphocyte responses, recent evidence indicates that CD4+ T cells are an equally critical component of the anti-tumour immune response. Successful immunity to cancer will therefore require activation of tumour-specific CD4+ T cells. Tumour antigens recognised by CD4+ T cells that are restricted by Major Histocompatibility Complex (MHC) class II are beginning to be defined in both murine and human tumours (Pardoll & Topalian 1998). Tumour antigens are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognise the tumour cell as abnormal. NK cells also kill tumorous cells in a similar way, especially if the tumour cells have fewer MHC class I molecules on their surface than normal; this is a common phenomenon with tumours (Hayakawa & Smyth 2006). Sometimes antibodies are generated against tumour cells allowing for their destruction by the complement system (Guevara-Patino et al 2003). Clearly, some tumours evade the immune system and go on to become cancers. Tumour cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells. Some tumour cells also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which suppresses the activity of macrophages and lymphocytes. In addition, immunological tolerance may develop against tumour antigens, so the immune system no longer attacks the tumour cells, tumours produce several factors, such as Prostaglandins (PGs), Interleukin (IL)-10, Vascular Endothelial Growth Factor (VEGF) and Transforming Growth Factor (TGF)-β , which may directly or indirectly inhibit the immune response and may hamper immunotherapy. (Frumento et al 2006). Paradoxically, macrophages can promote tumour growth when tumour cells send out cytokines that attract macrophages which then generate cytokines and growth factors that nurture tumour development. In addition, a combination of hypoxia in the tumour and a cytokine produced by macrophages induces tumour cells to decrease production of a protein that blocks metastasis and thereby assists spread of cancer cells (Stix 2007). Andersen MH, Schrama D, Thor Straten P, Becker JC (Jan 2006). “Cytotoxic T cells”. J Invest Dermatol 126 (1): 32–41. doi:10.1038/sj.jid.5700001. Boon T, van der Bruggen P (Mar 1996). “Human tumour antigens recognised by T lymphocytes”. J Exp Med 183 (3): 725–29. doi:10.1084/jem.183.3.725. ISSN 0022-1007. Frumento G, Piazza T, Di Carlo E, Ferrini S (Sep 2006). “Targeting tumour-related immunosuppression for cancer immunotherapy”. Endocr Metab Immune Disord Drug Targets 6 (3): 233–7. doi:10.2174/187153006778250019. Gerloni M, Zanetti M. (Jun 2005). “CD4 T cells in tumour immunity”. Springer Semin Immunopathol 27 (1): 37–48. doi:10.1007/s00281-004-0193-z. Guevara-Patino JA, Turk MJ, Wolchok JD, Houghton AN (2003). “Immunity to cancer through immune recognition of altered self: studies with melanoma”. Adv Cancer Res. 90: 157–77. Hayakawa Y, Smyth MJ. (2006). “Innate immune recognition and suppression of tumours”. Adv Cancer Res 95: 293–322. doi:10.1016/S0065-230X(06)95008-8. ISSN 0065-230X. Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007 May;117(5):1175-83. Pardoll DM, Topalian SL. The role of CD4+ T cell responses in antitumour immunity. Curr Opin Immunol. 1998 Oct;10(5):588-94. Stix G. Sci Am. 2007 Jul;297(1):60-7. Smyth MJ, Cretney E, Kershaw MH, Hayakawa Y. Cytokines in cancer immunity and immunotherapy. Immunol Rev. 2004 Dec;202:275-93. Wilhemina Hoedeman Executive Director COO CHM/RD Pty Ltd Panaxea Australia Panaxea Publishing 74-78 Brandling Street Sydney 2015 Australia Ph. Int + 612 9519 2233 F. Int. + 612 95192 633

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