Targeting phosphorylated p53 to elicit tumor-reactive T helper responses against head and neck squamous cell carcinoma

Abstract

The human T cell receptor is capable of distinguishing between normal and post-translationally modified peptides. Because aberrant phosphorylation of cellular proteins is a hallmark of malignant transformation, the expression of the phosphorylated epitope could be an ideal antigen to combat cancer without damaging normal tissues. p53 activates transcription factors to suppress tumors by upregulating growth arrest and apoptosis-related genes. In response to DNA damage, p53 is phosphorylated at multiple sites including Ser33 and Ser37. Here, we identified phosphorylated peptide epitopes from p53 that could elicit effective T helper responses. These epitope peptides, p53 22-41/Phospho-S33 and p53 22-41/Phospho-S37 , induced T helper responses against tumor cells expressing the phosphorylated p53 protein. Moreover, chemotherapeutic agents augmented the responses of such CD4 T cells via upregulation of phosphorylated p53. The upregulation of phosphorylated p53 expression by chemotherapy was confirmed in in vitro and xenograft models. We evaluated phosphorylated p53 expression in the clinical samples of oropharyngeal squamous cell carcinoma and revealed that 13/24 cases (54%) were positive for phosphorylated p53. Importantly, the lymphocytes specific for the phosphorylated p53 peptide epitopes were observed in the head and neck squamous cell cancer (HNSCC) patients. These results reveal that a combination of phosphorylated p53 peptides and chemotherapy could be a novel immunologic approach to treat HNSCC patients.

Chemokine-Cytokine Networks in the Head and Neck Tumor Microenvironment

“…Using bioinformatics analysis of the Cancer Genome Atlas (TCGA) data, we also observed many cytokines and chemokines deregulated in HNSCC (Figure 2). Consistent with these observations, previous studies have also reported a decrease in Th1 and increase in Th2 cytokine levels [117,118] such as IL-4, IL-6, IL-8, IL-10, GM-CSF, VEGF, prostaglandin E2 (PGE2), and bFGF during the development and progression of HNSCC [119][120][121]. While the increased IL-10, IL-17A, and IL-22 levels, and decreased IFN-γ expressions are collaborated with the loco-regional metastasis [122,123], increased VEGF, FGF, and IL-8 expression contribute to tumorigenesis, metastasis, and HNSCC angiogenesis [16,124,125].…”

A New Chalcone Derivative C49 Reverses Doxorubicin Resistance in MCF-7/DOX Cells by Inhibiting P-Glycoprotein Expression

“…The expression of apoptins in the downstream of PI3K/Akt signaling pathway was explored, and the results showed that the expression of Caspase-3 and Caspase-9 in the combinational treatment group were remarkably upregulated while the expression of Bcl-2 was markedly downregulated (Figure 6D). Some reports have shown an increase in phosphorylated p53 was induced by treatment with chemotherapeutic reagents in vitro and in murine xenograft models (Ohara et al, 2018). In our present study, there is no change in the expression level of p53 among the different groups, but its phosphorylated expression have been changed after C49 treatment in MCF-7/DOX cells (Figure 6D).…”

Fundamental and Essential Knowledge for Pathologists Engaged in the Research and Practice of Immune Checkpoint Inhibitor-Based Cancer Immunotherapy

“…In addition, the identification of hotspot mutation-derived neo-antigens and their application for tailored neo-antigen therapy has become reality (28). Regarding antigens derived from cancer-specific aberrant post-translational modifications, protein phosphorylation can alter the structure of self-peptides to generate tumor-specific epitopes (29)(30)(31). The functional relevance and efficient detection of these reproducible neo-antigens are under investigation.…”