Abstract
Transcription factor and oncosuppressor protein p53 is considered as one of the most promising molecular targets that remains a high-hanging fruit in cancer therapy. TP53 gene encoding the p53 protein is known to be the most frequently mutated gene in human cancers. The loss of transcriptional functions caused by mutations in p53 protein leads to deactivation of intrinsic tumor suppressive responses associated with wild-type (WT) p53 and acquisition of new pro-oncogenic properties such as enhanced cell proliferation, metastasis and chemoresistance. Hotspot mutations of p53 are often immunogenic and elicit intratumoral T cell responses to mutant p53 neoantigens, thus suggesting this protein as an attractive candidate for targeted anti-cancer immunotherapies. In this review we discuss the possible use of p53 antigens as molecular targets in immunotherapy, including the application of T cell receptor mimic (TCRm) monoclonal antibodies (mAbs) as a novel powerful approach.
Highlights
The tumor suppressor p53 is a protein that performs its cellular functions through transcriptional regulation of genes involved in DNA repair, senescence and apoptosis
Human cancer is often accompanied by genetic mutations, especially in TP53, with each patient carrying their own set of mutations resulting in neoantigen-specific T cell responses
The peptide neoantigens from a proteolytically processed mutant p53 protein are presented by antigen-presenting cell (APC) to B and T cells to activate the immune response
Summary
The tumor suppressor p53 is a protein that performs its cellular functions through transcriptional regulation of genes involved in DNA repair, senescence and apoptosis. Some immune-associated cellular mechanisms triggered by p53 become dysfunctional when the protein is mutated, and can result in enhanced neoangiogenesis and ECM remodeling, disruption of innate tumor immunity, genotoxic stress response of the toll-like receptor (TLR) pathway, formation of pro-tumor macrophage signature and altered cell-mediated immunity in cancer [12]. Human cancer is often accompanied by genetic mutations, especially in TP53, with each patient carrying their own set of mutations resulting in neoantigen-specific T cell responses This knowledge can be utilized to develop personalized therapies depending on the tumor genetic profile [20]. Recent data suggested that the HLA affinity to neoantigen peptides may differ significantly depending on the mutation status unrelated to genotype variation and couldn’t be FIGURE 2 | Regulation of immune system functions by p53 protein in tumor cells. ALT801, a biologic drug composed of interleukin-2 (IL-2) genetically fused to a soluble humanized TCR specific to a p53-derived antigen, is currently in phase II clinical trials in combination with gemcitabine (bladder cancer) and cisplatin (metastatic melanoma) [37, 38]
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