Cure Alveolar Soft Part Sarcoma International (iCureASPS)

The Role of Neoantigens in Naturally Occurring and Therapeutically Induced Immune Responses to Cancer

Article information

Adv Immunol. Author manuscript; available in PMC 2018 Aug 12.
Published in final edited form as:
Adv Immunol. 2016; 130: 25–74.
Published online 2016 Feb 10. doi: 10.1016/bs.ai.2016.01.001

Abstract

Definitive experimental evidence from mouse cancer models and strong correlative clinical data gave rise to the Cancer Immunoediting concept that explains the dual host-protective and tumor-promoting actions of immunity on developing cancers. Tumor-specific neoantigens can serve as targets of spontaneously arising adaptive immunity to cancer and thereby determine the ultimate fate of developing tumors. Tumor-specific neoantigens can also function as optimal targets of cancer immunotherapy against established tumors. These antigens are derived from nonsynonymous mutations that occur during cellular transformation and, because they are foreign to the host genome, are not subject to central tolerance. In this review, we summarize the experimental evidence indicating that cancer neoantigens are the source of both spontaneously occurring and therapeutically induced immune responses against cancer. We also review the advances in genomics, bioinformatics, and cancer immunotherapy that have facilitated identification of neoantigens and have moved personalized cancer immunotherapies into clinical trials, with the promise of providing more specific, safer, more effective, and perhaps even more generalizable treatments to cancer patients than current immunotherapies.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087548/

Neoantigens Generated by Individual Mutations and Their Role in Cancer Immunity and Immunotherapy

Abstract

Recent preclinical and clinical studies have proved the long-standing hypothesis that tumors elicit adaptive immune responses and that the antigens driving effective T-cell response are neoantigens, i.e., peptides that are generated from somatically mutated genes. Hence, the characterization of neoantigens and the identification of the immunogenic ones are of utmost importance for improving cancer immunotherapy and broadening its efficacy to a larger fraction of patients. In this review, we first introduce the methods used for the quantification of neoantigens using next-generation sequencing data and then summarize results obtained using these tools to characterize the neoantigen landscape in solid cancers. We then discuss the importance of neoantigens for cancer immunotherapy using checkpoint blockers, vaccination, and adoptive T-cell transfer. Finally, we give an overview over emerging aspects in cancer immunity, including tumor heterogeneity and immunoediting, and give an outlook on future prospects.

Keywords: next-generation sequencing, immunoediting, tumor heterogeneity, somatic mutations, cancer vaccines

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712389/

Neoantigen: A New Breakthrough in Tumor Immunotherapy

Cancer immunotherapy works by stimulating and strengthening the body’s anti-tumor immune response to eliminate cancer cells. Over the past few decades, immunotherapy has shown remarkable efficacy in the treatment of cancer, particularly the success of immune checkpoint blockade targeting CTLA-4, PD-1 and PDL1, which has led to a breakthrough in tumor immunotherapy. Tumor neoantigens, a new approach to tumor immunotherapy, include antigens produced by tumor viruses integrated into the genome and antigens produced by mutant proteins, which are abundantly expressed only in tumor cells and have strong immunogenicity and tumor heterogeneity. A growing number of studies have highlighted the relationship between neoantigens and T cells’ recognition of cancer cells. Vaccines developed against neoantigens are now being used in clinical trials in various solid tumors. In this review, we summarized the latest advances in the classification of immunotherapy and the process of classification, identification and synthesis of tumor-specific neoantigens, as well as their role in current cancer immunotherapy. Finally, the application prospects and existing problems of neoantigens were discussed.

https://www.frontiersin.org/articles/10 ... 72356/full

Neoantigen: A New Breakthrough in Tumor Immunotherapy-continued

Introduction


The human immune system helps us avoid infections and many diseases and protects us from cancer (1, 2). With the ability to recognize its own and non-self substances, the body’s immune system can produce natural immune tolerance to its own components and eliminate non-self foreign bodies to maintain the internal environment’s stability (3). Cancer occurs when normal cells change and begin to lose control. Since cancer cells are derived from normal cells and are indistinguishable from normal cells, the immune system’s ability to recognize cancer cells is minimal (4, 5). Cancer cells can avoid being attacked by the immune system when the immune system mistakenly thinks tumor cells are self-components. The surveillance of the immune system is also progressively weakened by mutations in the tumor. Tumor cells that activate the immune system are gradually screened out until they produce tumor molecules that are not recognized by the immune system. This process is also known as immunoediting of tumor. In this way, tumor cells successfully escape the damage of the immune system and have a chance to develop . What’s more, because cancer cells themselves can also release many substances that block the immune system, tumor immune response is often selectively suppressed around the tumor tissue (6, 7), which explains the ineffectiveness of immunotherapy in many patients: it is the failure to activate the immune response around the tumor tissue rather than the inability to activate the immune response systematically (6–9). In addition, inflammation can promote the development of tumors. Inflammation can release a large number of immunosuppressive cytokines locally in tumor tissue and suppress the immune system through a variety of ways. So cancer still could be caused even with a normal immune system. To overcome this problem, researchers have been looking for ways to help the immune system enhance its antitumor immune responses and improve its capacity to suppress tumor. In recent years, immunotherapy has developed rapidly and become a mature cancer treatment strategy in addition to surgery, chemotherapy and radiotherapy. Immunotherapy has shown a significant therapeutic effect in many human malignant tumors by using the immune system to eliminate cancer cells (10).

With the wide application of high-throughput omics and the development of neoantigen prediction technology, immunotherapy based on neoantigen has become a new research hotspot. Neoantigens are mainly tumor-specific antigens generated by mutations in tumor cells, which are only expressed in tumor cells (11). Neoantigens can also be produced by viral infection, alternative splicing and gene rearrangement (12–14). They are ideal targets for T cells to recognize cancer cells and can stimulate strong anti-tumor immune response. Studies in the past five years have shown that neoantigens play a key role in tumor immunotherapy. The identification, screening and identification of neoantigens accelerate the development of personalized immunotherapy for tumor patients, which will benefit more patients (15). As more scientific and clinical data reveal the remarkable effects of neoantigen-based vaccine therapies in a variety of cancer types, there is ample reason to believe that neoantigen-based therapies will be a promising area of cancer immunotherapy.

NEE-oh-AN-tih-jen) A new protein that forms on cancer cells when certain mutations occur in tumor DNA. Neoantigens may play an important role in helping the body make an immune response against cancer cells.


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