Identification of human antitumor cytotoxic T lymphocytes epitopes of recoverin, a cancer-associated retinopathy antigen, possibly related with a better prognosis in a paraneoplastic syndrome

Melanocytes, melanoma and photoreceptor cells are of neuroectodermal origin and have a certain sensitivity to light. In this study, we present evidence for photoreceptor proteins that are responsible for visual transduction and its regulation function as a new class of cancer antigens in melanoma. Visual rhodopsin, transducin, cGMP-phosphodiesterase 6, cGMP-dependent channels, guanylyl cyclase, rhodopsin kinase, recoverin and arrestin are expressed in melanoma and can induce antibody responses in patients. Melanocytes also express mRNA of all photoreceptor genes besides transducin, but were devoid of the corresponding protein, which was tested for rhodopsin, cGMP-phosphodiesterase, guanylyl cyclase and recoverin. Furthermore, we show for the first time that some healthy tissues express mRNA of these genes, but never protein. Expression profiles and autoantibody responses were confirmed in the MT/ret and the HGF tg /Ink4a 2/2 transgenic mouse melanoma models. We propose a molecular transition of cancer-retina antigens from mRNA expression in melanocytes to protein expression in melanoma. Our work provides the basis for analyzing regulation of photoreceptor gene expression in normal and malignant cells as well as possible therapeutic tumor targeting using the newly defined class of cancer-retina antigens. ' 2006 Wiley-Liss, Inc.Key words: tumor antigens; photoreceptor proteins; melanoma; Ret; hepatocyte growth factor/scatter factor; melanocytes Phototransduction is a biochemical process by which the photoreceptor cells generate electrical signals in response to the absorption of photons (reviewed in [1][2][3] ). This process occurs in the outer segments of rod and cone photoreceptor cells. So far in health, the proteins involved in this process have been described to be expressed only in retina and pineal glands. 4 However, in cancer the photoreceptor protein recoverin has also been detected in various types of malignant tumors, most frequently in lung carcinomas. 5 Recoverin is expressed in about 75% of lung cancer tissues, and serum autoantibodies against recoverin were found in about 20% patients with lung cancer. 6 Moreover, recent screening attempts for identifying antigens associated with malignant melanoma have unraveled rhodopsin and arrestin to be transcribed in melanoma cell lines, and autoantibodies against these proteins have been found in sera of melanoma patients by SEREX. 7 By analogy with cancer-testis antigens, we proposed to set off a new group of cancer antigens-cancer-retina antigens with recoverin as the first member of this group. 8 Which proteins involved in phototransduction may be additional candidates for cancer-retina antigens? After photon capture, each molecule of bleached rhodopsin activates hundreds of molecules of the G-protein transducin by catalyzing the GDP/GTPexchange on the transducin molecule. GTP-containing transducin in turn activates the effector enzyme cGMP-phosphodiesterase 6 (PDE6), thus allowing hydrolysis of the photoreceptor secondary messenger, cGMP. The decrease in...

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“…26 Thus, the group of cancer-retina antigens shares substantial features with the wellknown group of cancer-testis antigens (Fig. 5).…”

Section: Discussionmentioning

confidence: 85%

Photoreceptor proteins as cancer‐retina antigens

Bazhin

Schadendorf

Willner

et al. 2006

Intl Journal of Cancer

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“…CTLs were induced from PBMCs of cancer patients by using autologous dendritic cells and phytohemagglutinin (PHA) blasts as antigen-presenting cells (APC; refs. 23,24). Briefly, PBMCs (1 Â 10 7 -1 Â 10 8 ) were isolated from blood of cancer patients by using Lymphoprep (Nycomed) and then separated into CD14 + and CD14 -cells by using MACS separation system (Miltenyi Biotech) and anti-CD14 monoclonal antibody coupled with magnetic microbeads according to the manufacturer's instruction.…”

Section: Translational Relevancementioning

confidence: 99%

Identification of an Immunogenic CTL Epitope of HIFPH3 for Immunotherapy of Renal Cell Carcinoma

Sato¹,

Torigoe²,

Hirohashi³

et al. 2008

Clinical Cancer Research

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Purpose: CD8 + CTLs have an essential role in immune response against tumor. Although tumorassociated antigens have been identified in renal cell carcinoma (RCC), few of these are commonly shared and investigated as therapeutic targets in the clinical medicine. In this report, we show that HIFPH3, a member of prolyl hydroxylases that function as oxygen sensor, is a novel tumor antigen and HIFPH3-specific CTLs are induced from peripheral blood lymphocytes of RCC patients. Experimental Design: Expression of HIFPH3 was examined by reverse transcription-PCR and immunostaining with anti-HIFPH3 antibody. To identify HLA-A24-restricted T-cell epitopes of HIFPH3, eight peptides were selected from the amino acid sequence of this protein and screened for their binding affinity to HLA-A24. Peptide-specific CTLs were induced by stimulating peripheral blood lymphocytes of HLA-A24-positive RCC patients with these peptides in vitro. HLA-A24-restricted cytotoxicity of the CTLs against HIFPH3 + RCC lines was assessed by chromium release assay. Results: HIFPH3 was overexpressed in many RCC cell lines and primary RCC tissues, whereas it was not detectable in normal adult tissues by reverse transcription-PCR. Of the eight peptides that contained HLA-A24-binding motif, HIFPH3-8 peptide (amino acid sequence, RYAMTV-WYF) could induce the peptide-specific CTLs from 3 of 6 patients with HIFPH3-positive RCC. Furthermore, HIFPH3-8 peptide-specific CTLs showed cytotoxicity against HIFPH3 + RCC cell lines in a HLA-A24-restricted manner. Conclusions: HIFPH3 may be a target antigen in immunotherapy for RCC and HIFPH3-8 peptide could be used as a peptide vaccine for HLA-A*2402 + /HIFPH3 + RCC patients.

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“…that recoverin-specific cytotoxic T lymphocytes (CTL) exist in the peripheral circulation of CAR patients, and these CTL can recognize tumor-expressing recoverin (Maeda et al 2001a). These observations correspond well with the favorable prognosis characteristic of malignant tumors underlying CAR.…”

Section: Discussionmentioning

confidence: 99%

“…However, in contrast, we have recently found that aberrant expression of retina-specific recoverin occurred in more than 50% of several kinds of cancer cells, and their cell lines obtained from non-CAR cancerous patients (Maeda et al 2000;Maeda et al 2001a). Furthermore, we have made the following experimental observations: 1) immunofluorescence labeling by affinity purified recoverin antibody revealed the immunoreactivity toward recoverin as a granular pattern within the cancer cells (Maeda et al 2001b;Miyagawa et al 2003); 2) transfection with human recoverin cDNA of A549 cells from human lung adenocarcinoma, which did not express recoverin, exhibited a significant reduction in cell proliferation (Maeda et al 2000); 3) significant changes were observed in protein phosphorylation patterns in cytosol of A549 cells upon addition of purified recoverin in a calcium-dependent manner (Maeda et al 2001b) recoverin-specific cytotoxic T lymphocytes (CTL) exist in the peripheral circulation of CAR patients, and these CTL can recognize tumor-expressing recoverin (Maeda et al 2001a). …”

confidence: 93%