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Targeting p53 for adoptive T-cell immunotherapy
1Department of Surgery, City of Hope National Medical Center, Duarte, California 91010, USA.
Abstract:
p53 gene mutations occur in most human cancers and result in an altered protein product that accumulates within the cell. Although the observed endogenous human CTL response to p53 is weak, high-affinity, human p53-specific CTLs have been generated from HLA A2.1 transgenic mice immunized with human CTL epitope peptides. In this study, we examine the ability of HLA A2.1-restricted and human p53-specific CTLs from HLA A2.1 transgenic mice to suppress the growth of p53-overexpressing human tumors in severe combined immunodeficient (SCID) mice. In vitro, murine p53(149-157)-specific CTLs selectively lysed the p53-overexpressing pancreatic carcinoma cell line Panc-1 but did not recognize HLA A2.1- tumor cells or HLA A2.1+ normal human fibroblasts. Furthermore, in vivo, the growth of established human tumor xenografts in SCID mice was significantly reduced and survival was prolonged after the administration of p53-specific CTLs but not after the administration of control CTLs or PBS alone. Following treatment with p53(149-157)-specific CTLs, regressing Panc-1 tumors were infiltrated by the CD8+ CTLs, as demonstrated by immunohistochemistry. These findings suggest that p53(149-157)-specific and HLA A2.1-restricted murine CTLs suppress the growth of established Panc-1 tumors following adoptive transfer into SCID hosts and prolong their survival.
Insights
High-affinity T cells targeting the p53 tumor suppressor protein effectively suppressed tumor growth in mice. This study demonstrates the potential of p53-specific T cell therapy for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Cancer Therapy
Background:
- p53 gene mutations are prevalent in human cancers, leading to altered p53 protein accumulation.
- Endogenous human T cell responses to p53 are typically weak.
- Previous research generated high-affinity p53-specific T cells (CTLs) in HLA A2.1 transgenic mice.
Purpose of the Study:
- To investigate the efficacy of HLA A2.1-restricted, p53-specific CTLs in suppressing p53-overexpressing human tumors.
- To evaluate the therapeutic potential of adoptive T cell transfer in a mouse model.
Main Methods:
- Generated and characterized murine p53(149-157)-specific CTLs restricted by HLA A2.1.
- Assessed CTL-mediated lysis of p53-overexpressing Panc-1 cancer cells and control cells in vitro.
- Administered p53-specific CTLs to SCID mice bearing established human tumor xenografts.
Main Results:
- In vitro, p53(149-157)-specific CTLs selectively lysed p53-overexpressing Panc-1 cells but not control cells.
- In vivo, adoptive transfer of p53-specific CTLs significantly reduced tumor growth and prolonged survival in SCID mice.
- Immunohistochemistry confirmed infiltration of CD8+ CTLs into regressing Panc-1 tumors post-treatment.
Conclusions:
- HLA A2.1-restricted, p53(149-157)-specific murine CTLs effectively suppress established p53-overexpressing tumor growth.
- Adoptive transfer of these CTLs prolongs host survival in SCID mice.
- These findings support the therapeutic potential of p53-specific CTLs for cancer treatment.