Doytchinova and Flower BMC Immunology (2018) 19:11 https://doi.org/10.1186/s12865-018-0248-x REVIEW Open Access In silico prediction of cancer immunogens: current state of the art Irini A. Doytchinova1 and Darren R. Flower2* Abstract Cancer kills 8 million annually worldwide. Although survival rates in prevalent cancers continue to increase, many cancers have no effective treatment, prompting the search for new and improved protocols. Immunotherapy is a new and exciting addition to the anti-cancer arsenal. The successful and accurate identification of aberrant host proteins acting as antigens for vaccination and immunotherapy is a key aspiration for both experimental and computational research. Here we describe key elements of in silico prediction, including databases of cancer antigens and bleeding-edge methodology for their prediction. We also highlight the role dendritic cell vaccines can play and how they can act as delivery mechanisms for epitope ensemble vaccines. Immunoinformatics can help streamline the discovery and utility of Cancer Immunogens. Keywords: Cancer immunogens, Databases of cancer immunogens, Prediction of cancer immunogens, Dendritic cell-based vaccines, Multi-epitope vaccines Background deaths in women; about 25% of all deaths. Yet over half Cancer is a catch-all term for a constellation of diseases of the global cancer burden occurs in less well developed typically characterised by abnormal cell division. The countries. Lung, bowel, liver, and stomach, are the com- term cancer can be traced to the Greek physician monest cancers globally, equating to 4 in 10 deaths Hippocrates (460-370 BC), who used the terms carcin- worldwide. At about 1 in 10 cases, smoking-related lung oma and carcinos to refer to ulcer-forming tumours and cancer is the commonest male cancer. non-ulcer forming tumours. In Greek, these words refer A cancer can be classed as either “common” or “rare” to a crab. The Roman physician, Celsus (28-50 BC), based on relative prevalence. The precise threshold translated this to cancer, the Latin for crab. Galen between classes remains open. The US National Cancer (130-200 AD) used the Greek word oncos, meaning Institute (NCI) identifies “rare” as those cancers with a swelling to describe tumours. Almost all cells and tissues prevalence below 15 in 100,000 [2]. This means only 11 can become cancerous, but fortunately most cancers are adult cancers are defined as common in the US: pros- very rare. Yet cancer remains one of the prime health tate, breast, lung, bowl, cervical, bladder, rectum, ovary, issues of our time [1]. kidney, melanoma, and non-Hodgkin lymphoma [3]. In 2012, there were about 14 million new cancer cases Other adult cancers - about 25% of all adult cancers - worldwide and 8.2 million deaths. Deaths caused by can- are, by this definition, “rare” [3]. cer is very high in developed countries [1]. In 2014, the Driven by the financial exigencies governing drug US recorded 591,700 deaths from cancer, with approxi- discovery and development, effective cancer treatment is mately 197,233 deaths in women and 394,466 deaths in significantly skewed towards common cancers. As an men; about 22% of all deaths. The equivalent UK figures example, there are over 20 Category 1 intervention - were 163,000 deaths, or 450 deaths per day; with uniform consensus that intervention is appropriate and approximately 86,500 cancer deaths in men and 76,900 based on significant evidence - for prostate and breast cancer, the commonest cancers in men and women [4–6]. Yet none exist for say the bone cancers, chondrosarcoma * Correspondence: [email protected] 2School of Life and Health Sciences, Aston University, Aston Triangle, or chordoma, which affect under 1000 individuals annu- Birmingham B4 7ET, UK ally in the US [7–9]. Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Doytchinova and Flower BMC Immunology (2018) 19:11 Page 2 of 9 Survival varies considerably between different cancers. arm, mediated primarily by T cells. Historically, almost It ranges from 98% for testicular cancer to about 1% for all vaccine prophylactic responses have been mediated pancreatic cancer. Most common cancers have a 10-year by Antibodies. Each human has billions of potential anti- survival above 50%. Over 80% of those with cancers bodies capable of recognizing proteins and tagging them which are easy to treat and/or diagnose survive for 10+ for elimination. The individual ‘baseline’ for addressing years, yet less than 1 in 5 people with hard-to-treat or antigen challenge is the primary naïve antibody reper- hard-to-diagnose cancers survive for 10 years or more toire. The structural and sequence diversity of this base- [10]. Thus cancer remains a pivotal unmet medical need, line enables the immune system to recognize, at least driving both technical innovations and improved clinical weakly, a very large set of antigens. Unfortunately, only a practice, resulting in dramatic improvement in cancer treat- subset of Tumour Associated Antigens (TAAs) are ment. In the UK, mortality rates peaked in the 1980s, with amendable to the antibody mediated responses necessi- overall cancer mortality falling by 14% since the early tating the exploration of cellular immune mechanisms 1970s, with a 22% decrease in men and an 8% decrease in as a replacement or adjunct therapy. women. In the UK, mortality for all cancers is predicted to The effectiveness of potential therapeutic cancer vac- decrease by 15% in the period 2014-2035, reaching less than cines is often reduced by mechanisms in cancer patients 280 deaths per 1 hundred thousand by the year 2035 [10]. that suppress T-cells and antigen presenting cells According to somatic mutation theory, mutations in (APCs). Most cancer vaccines induce anti-tumour im- DNA and epi-mutations disrupt the programmed regula- mune responses when formulated with strong adjuvants, tion of cell division, upsetting the balance between pro- due to the general lack of immunogenicity exhibited by liferation and apoptotic cell death, resulting in excessive vaccines not derived from whole pathogens. Vaccination and uncontrolled division. Many mutations lead to can- against cancer takes several forms: DNA-based vaccines, cer, but most do not. The treatment of solid tumours in RNA-based vaccines, and DC-based vaccines. particular has changed dramatically in recent years due DNA vaccines: trials to evaluate the efficacy of to enhanced molecular diagnostics helping to identify a Inovio Pharmaceuticals combination vaccine INO-3112 burdening number of addressable oncogenic abnormalities are planned against cervical, head, and neck cancers including in-frame insertions/deletions and amplification (NCT02172911, NCT02163057) “http://ir.inovio.com/ or rearrangements and gene activating point mutations. news-and-media/news/press-release-details/2017/Inovio- Historically, cancer has been treated by small molecule Begins-Phase-3-Clinical-Trial-of-VGX-3100-for-the- drugs. A number of anti-cancer drugs are classed as Treatment-of-HPV-Related-Cervical-Pre-Cancer/default.aspx”. agents of so-called chemotherapy. These are typically INO-3112 contains plasmids encoding E6 and E7 (VGX- characterised by significant side-effects, as many affect 3100) [12] combined with DNA-based IL12 delivery cells indiscriminately. The main types of chemotherapy (INO-9012). Inovio’s preventive anti-HIV DNA vaccine, include DNA-damaging alkylating agents, including PENNVAX-G, used in a prime-boost protocol with structurally-simple reactive molecules such as Busulfan; altered pox virus vector, has a satisfactory safety and Antimetabolites, which compete with natural nucleo- immunogenicity profile [13]. This study should foment tides for incorporation into DNA or RNA, impairing design of anti-cancer therapeutic vaccines by exploring DNA replication, such as 5-fluorouracil; Anti-tumour prime-boost regimens using DNA vaccines and viral antibiotics, such as complex natural product Epirubicin; boosts. The Vaccibody-developed DNA-based vaccine Topoisomerase inhibitors, which interfere with DNA VB10.16 targets HPV16 “http://www.vaccibody.com/ unzipping prior to replication, such as Topotecan; vb10-16/”. A trial (NCT02529930) is set to launch; if suc- Mitotic inhibitors, such as plant-derived natural product cessful it should provide an innovative and much needed Paclitaxel; and Corticosteroids, such as Prednisone [11]. non-invasive way to treat HPV-induced cervical cancers. Other, more targeted therapies are now appearing. Preci- RNA vaccines: Sahin’s group pioneered use of lipid- sion medicine can be defined as therapy individualised based positively-charged nanoparticles delivering RNA to each tumour, achieving this by exploiting quantifiable encoding TAAs, to target DCs in vivo and thus simulate genetic alterations as de fact predictive biomarkers and/ an anti-viral response [14]. This is currently undergoing or as therapeutic or prophylactic