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Vaccines and Other Immunological Approaches for Cancer Immunoprevention

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Vaccines and Other Immunological Approaches for Cancer Immunoprevention Current Drug Targets, 2011, 12, 1957-1973 1957 Vaccines and Other Immunological Approaches for Cancer Immunoprevention Pier-Luigi Lollini*,1, Giordano Nicoletti2, Lorena Landuzzi2, Federica Cavallo3, Guido Forni3, Carla De Giovanni4 and Patrizia Nanni4 1Department of Hematology and Oncological Sciences, University of Bologna; 2Rizzoli Orthopedic Institute, Bologna; 3Molecular Biotechnology Center, Department of Clinical and Biological Sciences, University of Turin; 4Department of Experimental Pathology, University of Bologna, Italy Abstract: The immune system effectively prevents cancer, whereas severe immunodepression increases its incidence. Cancer immunoprevention is a strategy based on the concept that enhancement of tumor immunity in healthy individuals reduces cancer risk. It can be viewed as a kind of chemoprevention. For cancer immunoprevention, the cancer universe can be neatly divided between tumors caused - directly or indirectly - by infectious agents and all other tumors. Immunoprevention of tumors caused by infectious agents is already implemented at the population level for hepatitis B virus (HBV)-related hepatocellular carcinoma and for tumors caused by human papillomaviruses (HPV), like cervical carcinoma. Now the challenge is to develop immunological strategies to prevent the bulk (>80%) of human tumor burden, unrelated to infections. Both vaccines against tumor antigens and immune modulators can prevent tumor onset in cancer- prone mice. These studies outlined the target antigens and the molecular and cellular mechanisms of cancer immunoprevention: a) the best target antigens are surface molecules controlling tumor growth and progression (oncoantigens); b) combinations of potent vaccines and nonspecific stimuli (adjuvants) yield the strongest protection; c) immunoprevention must start early in the natural history of tumors, before key progression events like the onset of carcinoma in situ; d) lifetime protection requires repeated boosts, to maintain a strong and steady immune response; e) antibodies and helper, rather than cytotoxic, T cells mediate long-term protection from tumor onset; f) immunoprevention can be combined with chemoprevention. The development of agents like tamoxifen, which went from cancer therapy to chemoprevention, could be a model for the translation of cancer immunoprevention from mice to humans. Keywords: Antibodies, cancer vaccines, ErbB2, immunoprevention, mammary carcinoma, oncoantigens, viral tumors. FROM IMMUNE SURVEILLANCE TO IMMUNO- a) The nude mutation primarily afflicts epithelial com- PREVENTION ponents, including the thymus, and the lack of an appro- priate thymic environment hampers the normal matura- Prevention of tumor onset and progression is a concern of tion of T cells; however, an extrathymic maturation all multicellular organisms. The diverse array of biological leads to the appearance of a few mature (though fre- strategies deployed to fend off exogenous and endogenous quently autoreactive) T cells; carcinogenic processes ranges from DNA repair and tumor suppressor genes to xenobiotic metabolism and skin pigmen- b) Athymic nude mice compensate their T cell scarcitywith tation. One issue is whether the immune system is part of a potentiation of natural killer (NK) cell activity. NK these strategies. In other words, does it play a significant role cells actively prevent tumor onset and diffusion. In sum- in the natural prevention of carcinogenesis? This question mary, and especially for long-term studies of sponta- was set forth in the 1960s by the theory of cancer immune neous or carcinogen-induced tumor onset, nude mice are surveillance, which defined the ability to identify and des- not bonafide immune deficient hosts; troy nascent tumors as a fundamental property of the c) Many immune mechanisms that affect cancer onset and immune system [1]. progression are only marginally disturbed by the In the 1970s, however, the theory received an apparently absence of a normal T cell population. deadly blow by the lack of an increase in tumor incidence in Indeed the new millennium saw a vindication of the athymic nude mice [2]. Being the maturation of T cells immune surveillance theory, thanks to the advent of gene- inhibited, athymic nude mice lacking T cell-mediated activi- tically-modified mice, which allowed the generation of ties should be more prone to cancer than immunocompetent defined immune defects. Mice with an intrinsic, stable and wild-type ones. We now know that athymic mice are not an complete T and B cell deficit were found to be more prone to appropriate animal model to study immune surveillance, for spontaneous or chemical carcinogenesis than wild-type mice, three main reasons [1]: and additional gene defects affecting natural immune responses exposed mice to the risk of more aggressive and precocious tumors [3]. These observations were repeatedly confirmed by distinct laboratories studying gene knockout *Address correspondence to this author at the Sezione di Cancerologia, mice of different kind. At present, diverse experimental Viale Filopanti 22, 40126 Bologna, Italy; Tel: +39051-209-4786. Fax: evidence endorses the basic tenet of the immune surveillance +39051-242-169, E-mail: [email protected] theory: the immune system protects the host from tumor 1 - 5 /11 $58.00+.00 © 2011 Bentham Science Publishers 873 5 92 1958 Current Drug Targets, 2011, Vol. 12, No. 13 Lollini et al. onset, and immune deficits are accompanied by an increased trate the intrinsic carcinogenic potency of inflammation. This risk of cancer [1, 4-6]. opens up novel perspectives of immunoprevention, based not only on anti-inflammatory treatments, but also on more In humans, studies were mostly confined to syndromes of immune-oriented strategies that strive to re-orient the acquired immune deficiencies, since life expectancy in children with severe primary immune deficiencies was too immune response from pro-carcinogenic, frustrated chronic inflammation to tumor-preventive immune responses [11- short to study long-term tumor incidence. Thus we have 13]. mainly information concerning partial and variable immune deficiencies, like AIDS and post-transplant immune sup- The main perspectives in cancer immunoprevention are: pression. Nonetheless, human data confirm an increase in 1. Vaccines to prevent infection, especially chronic tumor incidence in immunodeficient individuals, in a special infection, by carcinogenic viruses and other infectious way for what concerns lymphoid tumors and tumors related agents; to viral infections, such as Kaposi sarcoma (human herpes virus-8) and anogenital carcinomas (HPV) [7], whereas the 2. Strategies to diminish chronic inflammation or to incidence of prevalent tumor types (e.g. breast, prostate and convert it into a beneficial immune response; colorectal carcinomas) is mostly indistinguishable from that 3. Induction of protective immune responses against of the general population. Among the “big killers”, only lung tumors unrelated to infectious agents, which we will cancer is increased in immunodeficient individuals, however call here collectively “non-infectious tumors”. many confounding factors prevent the establishment of a straightforward relationship with immune surveillance [7]. Here we will deal mainly with the first and third, because other reviews in this issue of Current Drug Targets deal with The increase of virus-related cancers in immune deficien- inflammation, and at present it is not clear whether the cies has become a cornerstone of tumor and viral immuno- conversion of chronic inflammation into protective immunity logy, now leading to novel etiological hypotheses through might be addressed by original strategies, or more likely will reverse reasoning: a viral or infectious etiology for a given be based on various combinations of the other approaches tumor histotype can be postulated and investigated on the described here. basis of a high incidence among immunodeficient popula- tions [8, 9]. Two major differences separate immunoprevention of infectious and non-infectious tumors: a) prevention of To summarize, it is now evident that the immune system infectious tumors is a type of primary prevention, aimed at contributes to the prevention of cancer onset. Hosts with a removing risk factors, whereas prevention of non-infectious severe and stable immune deficiency experience a genera- tumors is at the interface between primary and secondary lized enhancement of carcinogenesis, though even transient prevention, because the typical target is a preneoplastic cell impairments of immune defences expose the host to the risk that has experienced carcinogenic hits; b) even more of specific tumor types, in particular those caused by infec- importantly, immunoprevention of infectious tumors is tious agents. Moreover, immune mechanisms can hold occult already implemented in human populations, whereas only cancer at bay for periods equivalent to the natural life span of promising preclinical results are available for non-infectious the individual, while a temporary immunodepression permits tumors. the tumor to progress [6, 10]. Natural cancer prevention mechanisms, from DNA repair to immunity, share common fundamental features: all limit IMMUNOPREVENTION OF INFECTIOUS TUMORS cancer development, but none is 100% efficient. Tumors Marek’s Disease eventually arise, because preventive systems become less efficient with aging, while the risk of cancer increases. Given the advancement of human applications, we will Importantly, most mechanisms
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