Engineering neoantigen vaccines to improve cancer personalized immunotherapy

Abstract

Immunotherapy treatments harnessing the immune system herald a new era of personalized medicine, offering considerable benefits for cancer patients. Over the past years, tumor neoantigens emerged as a rising star in immunotherapy. Neoantigens are tumor-specific antigens arising from somatic mutations, which are proceeded and presented by the major histocompatibility complex on the cell surface. With the advancement of sequencing technology and bioinformatics engineering, the recognition of neoantigens has accelerated and is expected to be incorporated into the clinical routine. Currently, tumor vaccines against neoantigens mainly encompass peptides, DNA, RNA, and dendritic cells, which are extremely specific to individual patients. Due to the high immunogenicity of neoantigens, tumor vaccines could activate and expand antigen-specific CD4+ and CD8+ T cells to intensify anti-tumor immunity. Herein, we introduce the origin and prediction of neoantigens and compare the advantages and disadvantages of multiple types of neoantigen vaccines. Besides, we review the immunizations and the current clinical research status in neoantigen vaccines, and outline strategies for enhancing the efficacy of neoantigen vaccines. Finally, we present the challenges facing the application of neoantigens.

Keywords: Cancer; Immunotherapy; Neoantigen; Personalized therapy; Vaccine.

Figure 1

Preparation of neoantigen vaccines. Obtain normal tissue and tumor tissue from cancer patients, then perform whole exons and RNA sequencing to detect mutations. Bioinformatics technology screen out candidate neoantigens. Immunogenic neoantigens are identified by in vivo and in vitro experiments. At last, various types of neoantigen vaccines are prepared to treat cancer patients.

Figure 2

Immune response to neoantigen vaccines. After vaccination, neoantigen vaccines are first recognized by APCs around the injection site. The APCs reach the draining lymph nodes through lymphatic vessels. In the lymph node, neoantigen-specific T cells are activated. Activated CD8+ and CD4+ T cells clone and arrive at the tumor site with the circulatory system, specifically killing tumor cells.

Figure 3

Mechanisms of immune escape. A) Mutant gene sequences are transcribed and translated into mutated proteins. After processing, the mutant peptides enter the endoplasmic reticulum. They bind MHC I or MHC II to form peptide-MHC molecular complexes, which are transported to the surface of tumor cells. Any abnormality in the process of neoantigen processing and presentation could result in immune escape. B) Overexpression of immune checkpoints restrains anti-tumor immune responses. C) Various components of tumor microenvironment are associated with the occurrence of immune escape.

Figure 4

Some factors affect the efficacy of neoantigen vaccines.