Oncogene (2015) 34, 6029–6039 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc REVIEW Emerging strategies for cancer immunoprevention JC Roeser1, SD Leach2 and F McAllister3 The crucial role of the immune system in the formation and progression of tumors has been widely accepted. On one hand, the surveillance role of the immune system plays an important role in endogenous tumor prevention, but on the other hand, in some special circumstances such as in chronic inflammation, the immune system can actually contribute to the formation and progression of tumors. In recent years, there has been an explosion of novel targeted immunotherapies for advanced cancers. In the present manuscript, we explore known and potential various types of cancer prevention strategies and focus on nonvaccine- based cancer preventive strategies targeting the immune system at the early stages of tumorigenesis. Oncogene (2015) 34, 6029–6039; doi:10.1038/onc.2015.98; published online 14 September 2015 INTRODUCTION Differences between chemoprevention and immunoprevention. As cancer is a collection of multiple complex individual diseases Whereas immunoprevention focuses on directly or indirectly that happen in different sites of the body and progress in different targeting the immune system, chemopreventive strategies utilize ways, a large amount of information is required to understand drugs or natural compounds to prevent cancer development.3 how to prevent each cancer type. Existing interventions for cancer Less than a dozen chemopreventive agents have been FDA prevention focus on the use of chemopreventive agents or approved: tamoxifen and raloxifene for breast cancer fi prevention,4,5 celecoxib for colorectal polyps prevention in vaccines designed and tested for prevention of speci c cancer 6,7 8,9 types. Cancer vaccines that aim to manipulate the patient’s own FAP, BCG and valrubicin for bladder cancer prevention and several topical agents for prevention of skin cancer in patients immune system to destroy existing cancer cells are called fl ‘therapeutic vaccines’.1 Cancer vaccines that target the immune with actinic keratosis: uorouracil, diclofenac, masoprocol and ingenol mebutate.10 system to prevent the development of cancer are called ‘prophylactic vaccines’ and could potentially be used for cancer immunoprevention. However, there are many other strategies to Differences between immunoprevention and immunotherapy prevent cancer aside from vaccines. In the present manuscript, we The term ‘immunoprevention’ refers to the manipulation of the will review existing and potential cancer prevention strategies and immune system for disease prophylaxis, while ‘immunotherapy’ is focus on nonvaccine approaches for the prevention of cancer reserved for the treatment of existing disease by targeting the targeting the immune system. immune system. ‘Immunoprevention’ or ‘immunoprophylaxis’ represent one of the most successful types of interventions ever developed. Preventive vaccines have practically eliminated infectious diseases such as polio. In contrast, immunotherapies Types of cancer interventions against chronic infectious diseases have not shown enough There are two global interventions to target cancer: preventive efficacy due to the mechanisms developed by infectious and therapeutic strategies (Table 1). Cancer prevention includes all pathogens to avoid recognition and elimination by the immune approaches that aim to reduce the risk and incidence of cancer. system. Until very recently, the same was believed about cancer There are two types of cancer-preventive strategies: primary and immunotherapies, with most of strategies failing due to the secondary. Primary cancer prevention focuses on health counsel- tolerance and escape of detection by the immune system.11 ing, education and environmental control to decrease exposure to However, in the past decade, huge advances have been made in risk factors.2 More than 30% of cancer deaths could be prevented the immunotherapy field, most of them based on a better by avoiding key risk factors, including tobacco use, an unhealthy understanding of the molecular events leading to tumor 12 diet, alcohol abuse, sexually transmitted HPV infections and so on. tolerance. Tobacco is the single most important risk factor for cancer causing 22% of global cancer deaths. Secondary cancer prevention Immunoprevention of tumors caused by infectious agents encompasses interventions leading to the diagnosis and control Two different types of tumors can be targeted by immunopreven- of cancer and precancerous lesions at the earliest stage possible, tion, tumors caused by infectious agents or the ones caused by including screening and active interventions. These active noninfectious agents. Effective vaccines are available for viruses prevention strategies can be further divided in two types: associated with cancer development. The vaccine against the chemoprevention and immunoprevention. hepatitis B virus initially developed for hepatitis prevention has 1Department of Oncology. Johns Hopkins University. Maryland, MD, USA; 2The David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA and 3Department of Clinical Cancer Prevention. The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Correspondence: Dr F McAllister, Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1360, Houston, TX 77030, USA. E-mail: [email protected] Received 8 December 2015; revised 25 February 2015; accepted 27 February 2015; published online 14 September 2015 Cancer immunoprevention JC Roeser et al 6030 Table 1. Modalities of cancer prevention and therapy Cancer Prevention Therapy Primary Secondary Chemo Targeted Immuno therapy therapy therapy Active Targeted Screening Therapeutic prevention immuno- vaccines activators Chemo Immuno prevention prevention Infectious Non infectious Prophylactic Immunomodulators vaccines Targeted Targeted Anti-inflammatories immuno-activators also been shown to reduce the incidence and mortality of liver antibodies to interferon (IFN)-γ in tumor-bearing mice or mice carcinoma.13,14 In 2006, the FDA approved two vaccines lacking the IFN-γ receptor showed accelerated tumor growth developed primarily for the prevention of cervical cancer compared with control mice.18,19 Studies using perforin-deficient associated with HPV infections: Gardasil (Merck) and Cervarix mice have shown increased susceptibility to both chemically (GlaxoSmithKline, Rixensart, Belgium). Gardasil is a quadrivalent induced and spontaneous cancer models.20 Mice lacking the vaccine that protects against four HPV types: HPVs 6, 11, 16 and recombinase-activating gene (RAG)-2 cannot somatically rear- 18. Cervarix is a bivalent vaccine against HPVs 16 and 18. These range lymphocyte antigen receptors and cannot produce 15 vaccines can reduce the incidence of cervical cancer by 70%. peripheral αβ T cells, B cells, NKT cells (NKTs) or γδ T. As RAG-2 is selectively expressed in the lymphoid system, RAG-2− / − mice Immunoprevention of tumors caused by noninfectious agents provided an appropriate model to exclusively study the effects of There are two kinds of approaches to noninfectious tumor host lymphocyte deficiency on tumor development. Following − / − immunoprevention: one that targets specific antigens (vaccines) subcutaneous injection of a chemical carcinogen RAG-2 mice or another that targets nonspecific immune components. The developed sarcomas at the injection site faster and with greater 21,22 drugs developed for the latter approach will be called ‘immune- frequency than strain-matched controls. Data about the role modulators’ in the present manuscript. At this point, immunopre- of immunosurveillance in cancer prevention are not only restricted 23 ventive approaches for tumors of non-infectious cause are at the to preclinical mouse models, but also exists in humans. As an preclinical level of development. Multiple transgenic mouse example of this, approximately a fourfold increase in the incidence models harboring activated oncogenes have been produced in of de novo malignant melanoma after organ transplantation has 24 the past decade and they can be used to test prevention been reported. In spite of that, tumors do develop in the strategies by targeting the immune system.16 presence of a functional immune system. The protection provided by the immune system may not be sufficient and immune- The immunosurveillance theory and implications for preventive strategies aiming to promote antitumor immune immunoprevention defenses may bring a proportional decrease in tumor incidence. In the 1950s, Thomas and Burnet developed the theory of tumor immunosurveillance in which they proposed that the immune Theory of immunoediting and implications for immunoprevention system protects against developing tumors by attacking abnormal The immunoediting theory later replaced the immunosurveillance cells before they progress to invasive malignancy. However, when theory to reflect the increasingly apparent dual role of immunity in this hypothesis was tested in CBA/H nude mice, the most not only preventing but also in sculpting the tumoral process. congenitally immunodeficient mice available in 1970s, mice were Dunn et al.25 proposed that the process of immunoediting was found to develop spontaneous tumors and methylcholanthrene- comprised by three phases and named them ‘three Es of cancer induced sarcomas