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Tumor Neoantigens: from Basic Research to Clinical Applications

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Tumor Neoantigens: from Basic Research to Clinical Applications Jiang et al. Journal of Hematology & Oncology (2019) 12:93 https://doi.org/10.1186/s13045-019-0787-5 REVIEW Open Access Tumor neoantigens: from basic research to clinical applications Tao Jiang1,4†, Tao Shi2†, Henghui Zhang3†,JieHu1, Yuanlin Song1, Jia Wei2*, Shengxiang Ren4* and Caicun Zhou4* Abstract Tumor neoantigen is the truly foreign protein and entirely absent from normal human organs/tissues. It could be specifically recognized by neoantigen-specific T cell receptors (TCRs) in the context of major histocompatibility complexes (MHCs) molecules. Emerging evidence has suggested that neoantigens play a critical role in tumor- specific T cell-mediated antitumor immune response and successful cancer immunotherapies. From a theoretical perspective, neoantigen is an ideal immunotherapy target because they are distinguished from germline and could be recognized as non-self by the host immune system. Neoantigen-based therapeutic personalized vaccines and adoptive T cell transfer have shown promising preliminary results. Furthermore, recent studies suggested the significant role of neoantigen in immune escape, immunoediting, and sensitivity to immune checkpoint inhibitors. In this review, we systematically summarize the recent advances of understanding and identification of tumor- specific neoantigens and its role on current cancer immunotherapies. We also discuss the ongoing development of strategies based on neoantigens and its future clinical applications. Keywords: Neoantigen, Immunotherapy, Immune escape, Immune checkpoint, Resistance Introduction polyomavirus (MCPyV)–related Merkel cell carcinoma Tumor neoantigen, or tumor-specific antigen (TSA), (MCC) and Epstein-Barr virus (EBV)–relatedheadandneck is the repertoire of peptides that displays on the cancers, any epitopes derive from open reading frames tumor cell surface and could be specifically recog- (ORFs) in the viral genome also contribute to the potential nized by neoantigen-specific T cell receptors (TCRs) source of neoantigens [6–8]. In recent years, emerging evi- in the context of major histocompatibility complexes dence has suggested that neoantigens play a pivotal role in (MHCs) molecules [1–5]. From an immunological tumor-specific T cell-mediated antitumor immunity. As sum- perspective, tumor neoantigen is the truly foreign marized in several elegant reviews [2, 4, 5, 9], this evidence protein and entirely absent from normal human or- includes, but is not limited to, (1) the occurrence of antitu- gans/tissues. For most human tumors without a viral mor immune response via T cell recognition of neoantigen, etiology, tumor neoantigens could derive from a var- (2) the relationship between tumor mutation/neoantigen bur- iety of nonsynonymous genetic alterations including den and clinical outcomes to immune checkpoint blockade, single-nucleotide variants (SNVs), insertions and dele- and (3) the promising antitumor effects of therapeutic vac- tions (indel), gene fusions, frameshift mutations, and cines or adoptive T cell transfer based on neoantigen. structural variants (SVs) [2, 5]. For virally associated Unlike neoantigens, another two common types of tumors, such as human papillomavirus (HPV)–related tumor antigens, named tumor-associated antigens (TAAs) cervical or oropharyngeal cancer, Merkel cell and cancer-germline antigens (CGAs), are not only expressed on the tumor cell surface, they would also be * Correspondence: [email protected]; [email protected]; found on healthy or immune-privileged tissues (especially [email protected] †Tao Jiang, Tao Shi and Henghui Zhang contributed equally to this work. reproductive tissues including testes, fetal ovaries, and 2The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School trophoblasts) with low levels of expression [3, 10, 11]. of Nanjing University, No. 321, Zhongshan Road, Nanjing 210008, China Therapeutic vaccines based on the TAAs or CGAs have 4Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, No. 507, Zheng Min obtained dismal results mainly due to the central and Road, Shanghai 200433, China peripheral tolerance mechanisms [12]. Moreover, high- Full list of author information is available at the end of the article © The Author(s). 2019 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. Jiang et al. Journal of Hematology & Oncology (2019) 12:93 Page 2 of 13 affinity TCRs for TAAs are preferentially depleted because analogous protection against tumor cells could be in- of positive selection, and the affinities of the remaining duced by first exposing mice to lethally irradiated tumor TCRs for TAAs are lower than those for neoantigens and cells. Their findings revealed that the immune system other foreign antigens [13]. In addition, since TAAs or can recognize and eliminate malignant cells. Ten years CGAs could still have low levels of expression in normal later, another group further found that mice were im- tissues, targeting them may result in severe autoimmune mune against a second challenge with the same tumor toxicities related to immune activation in non-target cells after resection of carcinogen-induced tumors, sup- tissues, such as severe hepatitis, colitis, rapid respiratory porting the idea of the existence of antitumor immunity failure, renal impairment, and even treatment-related [19]. Nevertheless, the nature of antigens that could death [14]. substantially trigger antitumor immune response was Theoretically, neoantigen is an ideal immunotherapy unclear during this period. Several decades later, De target because they are distinguished from germline and Plaen and colleagues reported a significant finding that could be recognized as non-self by the host immune antitumor T cells could recognize aberrant peptides system [5]. Neoantigen-specific immune reactions are derived from tumor-specific mutations in a methylcho- not easily subject to complex immune tolerance mecha- lanthrene (MCA)-induced mouse tumor model [20]. nisms. Additionally, it may be less likely to trigger They further identified the first T cell–recognized autoimmunity because they do not express on normal neoantigen by using a cDNA library screen. After that, a cells. Neoantigen-based therapeutic personalized vac- series of neoantigens derived from somatic mutations cines and adoptive T cell transfer have shown promis- were identified in various human tumors including ing preliminary results. Furthermore, recent studies melanoma and renal cell carcinoma [21, 22]. Another suggested the significant role of neoantigen in immune significant advance in our understanding of neoantigens escape, immunoediting, and sensitivity to immune occurred in the early twenty-first century, when Huang checkpoint inhibitors. et al. found nearly complete regression in a melanoma In this review, we systematically summarize the recent patient after infusion of a cell product with a high pro- advances of understanding and identification of tumor- portion of neoantigen-reactive T cells [23] and Lennerz specific neoantigens and its role on current cancer et al. reported that the T cells of the patient with melan- immunotherapies. We also discuss the ongoing develop- oma were reactive against five mutated peptides result- ment of strategies based on neoantigens and its future ing from somatic point mutations and T cells against clinical applications. We do hope that this review could mutated epitopes was clearly predominated over the help us better understand the ongoing development of response to TAAs [24]. Similarly, the Rosenberg group strategies based on neoantigens and its future clinical found that neoantigen-specific T cells could persist at high applications. levels in both the tumor and peripheral blood 1 month after adoptive transfer in a patient with melanoma that Historical overview in the understanding of tumor experienced a complete regression following adoptive neoantigens transfer of ex vivo–expanded autologous tumor-reactive Currently, it is well-known that the immune system tumor-infiltrating lymphocytes (TILs)[25]. Collectively, possesses an extraordinary ability to distinguish self from these studies provided initial evidence that neoantigens non-self, and recognize and target non-self antigens on play a vital role in the naturally occurring antitumor T cell abnormal cells [4]. However, our understanding of response. With the advent and wide application of tumor neoantigens and its important role in antitumor next-generation sequencing (NGS) technology, we have immune response is a long and tortuous process (Fig. 1). obtained a more and more profound understanding on We can go back to the late nineteenth century when tumor neoantigens. In 2012, two research groups inde- William Coley, father of cancer immunotherapy, firstly pendently and firstly applied NGS technology to iden- attempted to leverage the patient’s immune system to tify immunogenic neoantigens in mouse tumor models treat cancer [15, 16]. In spite of
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