Increased frequencies of CD8+ T lymphocytes recognizing wild‐type p53‐derived epitopes in peripheral blood correlate with presence of epitope loss tumor variants in patients with hepatocellular carcinoma

Abstract

Wild-type (WT) sequence p53 peptides are attractive candidates for broadly applicable cancer vaccines. The aim of this study was to evaluate the potential of a WT p53-based immunotherapeutic approach for patients with hepatocellular carcinoma (HCC). Circulating CD8 1 T cells specific for WT p53 [149][150][151][152][153][154][155][156][157] and WT p53 [264][265][266][267][268][269][270][271][272] HLA-A*0201 restricted epitopes were directly identified in the peripheral blood by the use of peptide/HLA-A2.1 tetramers in 24 HCC patients. Cytotoxic T lymphocyte (CTL) activity after WT p53 peptide-specific stimulation was assessed by analysis of granzyme B and interferon-gamma mRNA transcription, using a quantitative real-time polymerase chain reaction assay. Tumor immunophenotyping was performed to evaluate the p53 status, the expression of major histocompatibility complex (MHC) and costimulatory molecules in freshly isolated tumor cells. HCC patients exhibited significantly higher frequencies of WT p53-specific memory CD8 1 T cells and stronger WT p53-specific CTL activity, when compared with healthy controls. Increased frequencies of p53-specific CD8 1 T cells and their activity correlated with selective HLA-A2 allele loss and reduced costimulatory molecule expression of tumor cells. Moreover, augmented numbers of p53-specific T cells coincided with high MHC class II expression in tumor cells but were inversely related to the T status of the tumor node metastasis staging system. Our results indicate the existence of natural immunosurveillance and tumor immune evasion, involving a T cell response against WT p53 tumor antigen in patients with HCC. These findings may have important implications for the future development of cancer vaccines. ' 2006 Wiley-Liss, Inc.Key words: cytotoxic T lymphocyte; hepatocellular carcinoma; immunotherapy; p53; tumor escape Hepatocellular carcinoma (HCC) represents the third most common cause of cancer in the world, and its incidence continues to increase. 1,2 The 5-year disease-free survival rate after liver resection is extremely poor because of frequent tumor recurrence. 3,4 Recent strategies using liver transplantation for selected patients with early tumor stage have shown more promising results. 5,6 However, liver resection or local tumor ablation remain the sole treatment options for the vast majority of patients; both adjuvant systemic chemotherapy and hormonal treatment have failed to significantly impact on patient survival. 7 New adjuvant treatment modalities are therefore needed to lower the incidence of tumor recurrence in patients after liver resection or local tumor treatment. Previously, it has been reported that the adjuvant adoptive transfer of ex vivo activated autologous lymphocytes in patients, who underwent liver resection for HCC, was associated with significantly increased recurrence-free survival. 8 These findings underline the important role of the adaptive cellular immune response for survival in patients with HCC and provide the rationale for the development ...

Immunization with a P53 synthetic long peptide vaccine induces P53‐specific immune responses in ovarian cancer patients, a phase II trial

“…Here, we did not detect CD8 1 T-cell reactivity and this was not unexpected as the p53-specific CD8 1 T cell, but not the CD4 1 T cell repertoire is severely restricted by self tolerance and might only consist of lower affinity p53-specific CD8 1 T cells. 19,21 However, p53-specific CD8 1 T cells have been identified in cancer patients, 42,43 and we can thus not rule out the possibility that with the help of an effective p53-specific Th1 response also p53-specific CD8 1 T-cells are activated. In favor of this are our observations that only those cervical cancer patients who were able to mount an E7-specific Th1 response upon HPV16-SLP immunization were also able to mount E7-specific CD8 1 T-cell immunity.…”

Natural immunity to pluripotency antigen OCT4 in humans

“…Several studies have examined the presence of self-antigen reactive T cells in healthy individuals and patients with cancer or autoimmunity. Detection of T cells specific for MelanA/MART1 (CD8 + , naive), carcinoembryonic antigen (CD4, naive), wildtype p53 (CD8/CD4, naive), cyclin B1 (CD4/CD8, naive/memory), glutamic acid decarboxylase, and insulin (CD4/CD8, naive) was feasible in T cells from healthy individuals (17)(18)(19)(20)(21). However, none of these nor similar studies evaluated the immunogenicity of ES-restricted antigens in humans or mice, which may provide a potential mechanism for immune-mediated surveillance (22) against unrestrained growth of pluripotent cells, as well as GCT.…”

Healthy individuals have T-cell and antibody responses to the tumor antigen cyclin B1 that when elicited in mice protect from cancer

“…T cells could be expanded in vitro for self antigens such as the melanoma-associated chondroitin sulfate proteoglycan (30), cytochrome p450 1B1 (31), survivin (32,33), melanoma inhibitor of apoptosis protein (34), and tyrosinase related protein 1 (35). Additionally, detection of T cells specific for Melan-A/Mart-1 (CD8 ϩ , naïve), Her2/neu (CD8 ϩ , effector), CEA (CD4 ϩ , naïve/ignorant or suppressed), and wildtype p53 (CD8 ϩ , mostly CD45RA ϩ ) was possible even without in vitro expansion (36)(37)(38)(39). These and similar studies focused primarily on the difference in responses to these molecules between healthy individuals and cancer patients or on showing that T cells were not centrally deleted and could potentially be expanded by vaccination.…”