MHC-restricted phosphopeptides from insulin receptor substrate-2 and CDC25b offer broad-based immunotherapeutic agents for cancer.

Autor:	Zarling AL; Carter Immunology Center and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia., Obeng RC; Carter Immunology Center and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia., Desch AN; Carter Immunology Center and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia., Pinczewski J; Department of Pathology, University of Virginia, Charlottesville, Virginia. Human Immune Therapy Center, University of Virginia, Charlottesville, Virginia., Cummings KL; Carter Immunology Center and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia., Deacon DH; Human Immune Therapy Center, University of Virginia, Charlottesville, Virginia. Department of Surgery, University of Virginia, Charlottesville, Virginia., Conaway M; Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia., Slingluff CL Jr; Human Immune Therapy Center, University of Virginia, Charlottesville, Virginia. Department of Surgery, University of Virginia, Charlottesville, Virginia., Engelhard VH; Carter Immunology Center and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia. vhe@virginia.edu.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2014 Dec 01; Vol. 74 (23), pp. 6784-95. Date of Electronic Publication: 2014 Oct 08.
DOI:	10.1158/0008-5472.CAN-14-0043
Abstrakt:	Cancer cells display novel phosphopeptides in association with MHC class I and II molecules. In this study, we evaluated two HLA-A2-restricted phosphopeptides derived from the insulin receptor substrate (IRS)-2 and the cell-cycle regulator CDC25b. These proteins are both broadly expressed in multiple malignancies and linked to cancer cell survival. Two phosphopeptides, termed pIRS-21097-1105 and pCDC25b38-46, served as targets of strong and specific CD8 T-cell memory responses in normal human donors. We cloned T-cell receptor (TCR) cDNAs from murine CD8 T-cell lines specific for either pIRS-21097-1105 or pCDC25b38-46. Expression of these TCRs in human CD8 T cells imparted high-avidity phosphopeptide-specific recognition and cytotoxic and cytokine-secreting effector activities. Using these cells, we found that endogenously processed pIRS-21097-1105 was presented on HLA-A2(+) melanomas and breast, ovarian, and colorectal carcinomas. Presentation was correlated with the level of the Ser(1100)-phosphorylated IRS-2 protein in metastatic melanoma tissues. The highest expression of this protein was evident on dividing malignant cells. Presentation of endogenously processed pCDC25b38-46 was narrower, but still evident on HLA-A2(+) melanoma, breast carcinoma, and lymphoblastoid cells. Notably, pIRS-21097-1105-specific and pCDC25b38-46-specific TCR-expressing human CD8 T cells markedly slowed tumor outgrowth in vivo. Our results define two new antigens that may be developed as immunotherapeutic agents for a broad range of HLA-A2(+) cancers. (©2014 American Association for Cancer Research.)
Databáze:	MEDLINE
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