ABSTRACT
Advanced hepatocellular carcinoma has a high degree of malignancy and poor prognosis. Studies showed that there is a close relationship between the progression of hepatocellular carcinoma and the immune status in tumor microenvironment. Adoptive cell therapy showed anti-tumor effects and improve immunosuppression by infusing patients with activated specific immune cells, which become a central issue in tumor therapy and shown promising effects in the treatment of various malignant tumors, indicating great application potential. Adoptive cell therapy based on neoantigen may become a new hot spot in the treatment of hepatocellular carcinoma, and their application, safety and effectiveness evaluation, efficacy prediction and assessment have become urgent issues to be solved. The purpose of this article is to introduce the progress related to adoptive cell therapy for advanced hepatocellular carcinoma and elaborate the problems that need to be solved in the future.
ABSTRACT
Tumor-specific gene mutations might generate suitable neoepitopes for cancer immunotherapy that are highly immunogenic and absent in normal tissues. The high heterogeneity of the tumor genome poses a big challenge for precision cancer immunotherapy. Mutations characteristic of each tumor can help to distinguish it from other tumors. Based on these mutations' characteristic, it is possible to develop immunotherapeutic strategies for specific tumors. In this study, a tumor neoantigen prediction scheme was proposed, in which both the intracellular antigen presentation process and the ability to bind with extracellular MHC molecule were taken into consideration. The overall design is meritorious and may help reduce the cost for validation experiments compared with conventional methods. This strategy was tested with several cancer genome datasets in the TCGA database, and a number of potential tumor neoantigens were predicted for each dataset. These predicted neoantigens showed tumor type specificity and were found in 20% to 70% of cancer patients. This scheme might prove useful clinically in future.
Subject(s)
Humans , Antigens, Neoplasm , Computational Biology , Genome, Human , Immunotherapy , Mutation , NeoplasmsABSTRACT
Objective@#To predict the tumor neoantigen peptides in hepatocellular carcinoma (HCC), and examine their specific immune effects against the tumor cells without injury to normal cells.@*Methods@#The data of whole-genome sequencing and exome sequencing of HCC tumor and matched non-tumor liver tissues were analyzed to confirm the HCC-associated somatic mutations. Based on the HLA phenotype of the patients, we used NetMHC software to predict the neoantigen epitopes with high binding affinity to their MHC-I molecules. The predicted peptides with mutation sites included were synthesized. GPL10687 platform was applied to examine the gene expression difference between tumor and normal tissues of the selected genes in GSE25097, one of the GEO databases. The quantitative real-time PCR (qRT-qPCR) and immunohistochemistry were used to confirm the expressions in tumors and normal tissues of the selected genes. By using the predicted peptides, we induced the generation of antigen-specific CD8+ cytotoxic T lymphocytes (CTLs) and examined their specific effects against tumor cells.@*Results@#The mutation frequency of TP53 (tumor protein p53) was 40%, and LAMA3 (Laminin Subunit Alpha 3) was 8% in the analyzed HCC tissues. In GSE25097 database, TP53 and LAMA3 mRNA levels in tumors were 1.57±0.02 and 1.37±0.10, which were significantly increased than those in matched no-tumor tissue (0.54±0.01 and 0.36±0.01, P<0.05). The differences of expression levels of TP53 and LAMA3 in tumor and no-tumor tissues were validated by using qRT-qPCR and immunohistochemistry in 10 HCC tissues. The mRNA levels of TP53 and LAMA3 in tumors were 0.24±0.03 and 0.13±0.06, which were significantly elevated than those in matched no-tumor tissue (0.11±0.01 and 0.01±0.01, P<0.05). Among the Chinese population, HLA-A2 and HLA-A11 and HLA-A24 accounted for 70%, representing the major MHC-I molecules. The CTLs induced by predicted peptides showed cytotoxicity to the targets pulsed with mutated peptide, with no effect on the target pulsed with normal peptide and on normal cells.@*Conclusions@#TP53 and LAMA3 existed relative higher mutation frequency in HCC, and expressed higher in tumor tissues. The induced CTLs by predicted peptides derived from mutation-associated protein could specific kill the target cells without injury to normal cells.
ABSTRACT
Neoantigens, as the products of gene mutations in tumor cells, are specific antigen expressed on the surface of tumor cells. They can be the targets of immuno-cell therapies with high specificity and safety. Immunotherapies based on tumor neoantigens became the new research hotspot as results of the applications of genomic sequencing technologies and the development of neoantigens prediction techniques. In this paper, the applied prospect of neoantigens in hematological malignancies is discussed based on the research progress in the last few years and the relevant reports from the 59th American Society of Hematology Annual Meeting.
ABSTRACT
Tumor neoantigens generated from somatic mutations can be presented by major histo-compability complex (MHC) molecules and elicit specific immune response against cancer. Therapeutic vac-cines and specific T cells targeting tumor neoantigens will realize the potential of precision immunotherapy in cancer treatment. Along with the development of methods for predicting neoantigens, individualized cancer immunotherapy strategies will be widely adopted. In the present review, we discuss the current state of the prediction approaches and clinical applications of neoantigens, as well as the challenges that remain to be ad-dressed in order to improve immunotherapy targeting neoantigens.