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...
Multiple reports have highlighted the importance of the local immunological cellular composition (i.e. the density of effector T cells and macrophage polarization state) in predicting clinical outcome in advanced metastatic stage of colorectal cancer. However, in spite of the general association between a high effector T cell density and improved outcome, our recent work has revealed a specific lymphocyte-driven cancer cell-supporting signal. Indeed, lymphocyte-derived CCL5 supports CCR5-positive tumor cell proliferation and thereby fosters tumor growth in metastatic liver lesions. Upon systematic analysis of CCR5 expression by tumor cells using immunohistochemistry, we observed that the intensity of CCR5 increases with primary tumor size and peaks in T4 tumors. In liver metastases however, though CCR5 expression intensity is globally heightened compared to primary tumors, alterations in the expression patterns appear, leading to "patchiness" of the stain. CCR5 patchiness is, therefore, a signature of liver metastases in our cohort (n = 97 specimens) and relates to globally decreased expression intensity, but does not influence the extent of the response to CCR5 inhibitor Maraviroc in patients. Moreover, CCR5 patchiness relates to a poor immune landscape characterized by a low cytotoxic-to-regulatory T cell ratio at the invasive margin and enriched cellular and molecular markers of macrophage M2 polarization. Finally, because higher numbers of PD-1-and CTLA-4-positive cells surround tumors with patchy CCR5 expression, one can speculate that these tumors potentially respond to immune checkpoint blockade. This hypothesis is corroborated by the prolonged disease-free survival and disease-specific survival observed in patients with low gene expression of CCR5 in metastases from two publically available cohorts. These observations highlight the complex role of the CCL5-CCR5 axis in CRC metastatic progression and warrant further investigations.
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