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A novel tumor antigen derived from enhanced degradation of Bax protein in human cancers

Nunes, Claudia Trindade, Miners, Kelly Louise, Dolton, Garry Michael, Pepper, Christopher John, Fegan, Christopher Daniel, Mason, Malcolm David and Man, Stephen Tzekwung 2011. A novel tumor antigen derived from enhanced degradation of Bax protein in human cancers. Cancer Research 71 (16) , pp. 5435-5444. 10.1158/0008-5472.CAN-11-0393

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Abstract

Cancer cells frequently exhibit defects in apoptosis, which contribute to increased survival and chemotherapeutic resistance. For example, genetic mutations or abnormal proteasomal degradation can reduce expression of Bax which limits apoptosis. In cancers where abnormal proteasomal degradation of Bax occurs, we hypothesized that Bax peptides that bind to human leukocyte antigen (HLA) class I molecules would be generated for presentation to CD8+ T cells. To test this hypothesis, we generated T cells against pooled Bax peptides, using the blood of healthy human donors. Although T-cell responses were of low frequency (0.15%), a CD8+ T-cell clone (KSIVB17) was isolated that optimally recognized Bax136–144 peptide (IMGWTLDFL) presented by HLA-A*0201. KSIVB17 was able to recognize and kill a variety of HLA-matched cancer cells including primary tumor cells from chronic lymphocytic leukemia (CLL). No reactivity was seen against HLA-matched, nontransformed cells such as PHA blasts and skin fibroblasts. Furthermore, KSIVB17 reactivity corresponded with the proteasomal degradation patterns of Bax protein observed in cancer cells. Taken together, our findings suggest a new concept for tumor antigens based on regulatory proteins that are ubiquitously expressed in normal cells, but that have abnormally enhanced degradation in cancer cells. Bax degradation products offer candidate immune antigens in cancers such as CLL in which increased Bax degradation correlates with poor clinical prognosis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: American Association for Cancer Research
ISSN: 0008-5472
Last Modified: 09 Jun 2018 19:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/29896

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