Abstract
Immunotherapy, including immune checkpoint blockade and chimeric antigen receptor T cells, is one of the most promising approaches to treat cancer. Vaccines have been effective in preventing cancers like liver cancer and cervical cancer with a viral etiology. Instead of preventing disease, therapeutic cancer vaccines mobilize the immune system to attack existing cancer. p53 is dysregulated in the majority of human cancers and is a highly promising target for cancer vaccines. Over twenty clinical trials have targeted p53 in malignant diseases using vaccines. In this work, we review the progress of vaccinations with p53 or its peptides as the antigens and summarize the clinical and immunological effects of p53-targeting vaccines from clinical trials. The delivery platforms include p53 peptides, viral vectors, and dendritic cells pulsed with short peptides or transduced by p53-encoding viruses. These studies shed light on the feasibility, safety, and clinical benefit of p53 vaccination in select groups of patients, implicating that p53-targeting vaccines warrant further investigations in experimental animals and human studies.
Highlights
TP53 gene encodes the transcription factor p53, one of the most important tumor suppressors
When immature Dendritic cells (DCs) recognize, uptake, and cross-present the antigens released by tumor cells, they shift to secondary lymphoid organs, where they activate CD4+ T cells or CD8+ T cells to trigger specific cytotoxic T lymphocytes (CTLs) responses against target cells (Wang et al, 2020a)
Both WT and mutant p53 epitopes can be presented on the cell surface in the context of MHC I molecules by antigen-presenting cells (APCs) for CD8+ T cell recognition (Houbiers et al, 1993)
Summary
TP53 gene encodes the transcription factor p53, one of the most important tumor suppressors. P53 becomes activated and stabilized to transcriptionally regulate target genes that are pivotal to various cellular processes, including cell cycle arrest, apoptosis, and DNA repair (Janic et al, 2018; Boutelle and Attardi, 2021). Missense mutations are the most common mutation type in cancer tissues, leading to mutant p53 accumulation in tumor cells Missense TP53 mutations are classified as contact or structural mutations Contact mutations, such as R248Q, R273H, and R273C, disrupt p53 DNA binding, resulting in loss of essential protein-DNA contacts. For tumors with WT p53, the approach is to suppress the interaction between p53 and MDM2/MDMX, inhibit the degradation of WT p53, and maintain the needed levels of p53 in cells, promote tumor suppression. P53 is an intracellular protein, making it inaccessible to antibodies
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