Identification of novel human leukocyte antigen‐A*11:01‐restricted cytotoxic T‐lymphocyte epitopes derived from osteosarcoma antigen papillomavirus binding factor

Abstract

Osteosarcoma is the most common malignancy of bone that affects young people. Neoadjuvant chemotherapy and surgery have significantly improved the prognosis. However, the prognosis of non‐responders to chemotherapy is still poor. To develop peptide‐based immunotherapy for osteosarcoma, we previously identified CTL epitopes derived from papillomavirus binding factor ( PBF ) in the context of human leukocyte antigen ( HLA )‐A2, HLA ‐A24 and HLA ‐B55. In the present study, we identified two novel CTL epitopes, QVT ( QVTVWLLEQK ) and LSA ( LSALPPPLHK ), in the context of HLA ‐A11 using a sequence of screenings based on the predicted affinity of peptides, in vitro folding ability of peptide/ HLA ‐A11 complex, reactivity of peptide/ HLA ‐A11 tetramer and interferon ( IFN )‐γ production of T cells that was induced by mixed lymphocyte peptide culture under a limiting dilution condition. CTL clones directed to QVT and LSA peptides showed specific cytotoxicity against HLA ‐A11 + PBF + osteosarcoma ( HOS ‐A11) cells. In contrast, another epitope, ASV ( ASVLSRRLGK ), could highly induce cognate tetramer‐positive CTL . This might be because the ASV peptide mimics the peptide ASV (R6Q) ( ASVLS Q RLGK ) derived from bacterial polypeptides, ROK family proteins. However, ASV ‐induced CTL did not show cytokine production against the cognate peptide. In conclusion, the CTL epitopes QVT and LSA peptides might be useful for the development of immunotherapy targeting PBF for patients with osteosarcoma.

Advancements in osteosarcoma management: integrating immune microenvironment insights with immunotherapeutic strategies

“…Moreover, Wiebel et al revealed an association between cell density and GD2 expression in osteosarcoma cells, finding that increased cell density enhanced the reactivity to GD2-specific CAR T cells, providing a basis for optimizing CAR T therapy ( Wiebel et al, 2021 ). In the search for innovative immunological targets, Li et al discerned two novel CTL epitopes derived from the osteosarcoma antigen papillomavirus binding factor (PBF) with immunostimulatory potential in the HLA-A11 context ( Li et al, 2019 ). Watanabe et al developed tumor-associated antigen-specific T cell receptor (TCR) multimers, particularly PBF TCR multimers, demonstrating high efficiency in recognizing naturally presented peptides and effectively identifying tumor-associated antigens on osteosarcoma cells, thus introducing novel strategies for immunotherapy ( Watanabe et al, 2019 ).…”

Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment

“… 261 Furthermore, various trials have also suggested that protein-based tumor vaccines, including those composed of tumor-rejection antigens and papillomavirus binding factors, can be used for specific immunotherapy in osteosarcoma and other malignant cancers due to shared overexpressed TAAs. 262 – 267 …”

“…261 Furthermore, various trials have also suggested that protein-based tumor vaccines, including those composed of tumor-rejection antigens and papillomavirus binding factors, can be used for specific immunotherapy in osteosarcoma and other malignant cancers due to shared overexpressed TAAs. [262][263][264][265][266][267] DCs, considered professional APCs, make up approximately 0.3% of the total cell population in the blood and can promote the proliferation and differentiation of CTLs. 268,269 Moreover, the quantity of DCs is strongly associated with the survival time of patients.…”

Metabolism and senescence in the immune microenvironment of osteosarcoma: focus on new therapeutic strategies

“…Tumor vaccines are mainly classified as autologous cancer and immune cell-based vaccines and non-cell-based vaccines ( 149 , 151 , 152 ). Among these types, immune cell-based vaccines make full use of innate immune cells to activate effector T lymphocytes ( 153 , 154 ). However, the feasibility of regulating migration and activation is a major issue, as these processes are regulated by immunosuppressive substances in the tumor microenvironment as well as by the quantity and quality of the patient’s immune effector cells ( 149 ).…”