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      Immunological Backbone of Uveal Melanoma: Is There a Rationale for Immunotherapy?

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          Abstract

          No standard treatment has been established for metastatic uveal melanoma (mUM). Immunotherapy is commonly used for this disease even though UM has not been included in phase III clinical trials with checkpoint inhibitors. Unfortunately, only a minority of patients obtain a clinical benefit with immunotherapy. The immunological features of mUM were reviewed in order to understand if immunotherapy could still play a role for this disease.

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          Mutations in GNA11 in uveal melanoma.

          Uveal melanoma is the most common intraocular cancer. There are no effective therapies for metastatic disease. Mutations in GNAQ, the gene encoding an alpha subunit of heterotrimeric G proteins, are found in 40% of uveal melanomas. We sequenced exon 5 of GNAQ and GNA11, a paralogue of GNAQ, in 713 melanocytic neoplasms of different types (186 uveal melanomas, 139 blue nevi, 106 other nevi, and 282 other melanomas). We sequenced exon 4 of GNAQ and GNA11 in 453 of these samples and in all coding exons of GNAQ and GNA11 in 97 uveal melanomas and 45 blue nevi. We found somatic mutations in exon 5 (affecting Q209) and in exon 4 (affecting R183) in both GNA11 and GNAQ, in a mutually exclusive pattern. Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. In contrast, we observed Q209 mutations in GNAQ in 55% of blue nevi, 45% of uveal melanomas, and 22% of uveal melanoma metastases. Mutations affecting R183 in either GNAQ or GNA11 were less prevalent (2% of blue nevi and 6% of uveal melanomas) than the Q209 mutations. Mutations in GNA11 induced spontaneously metastasizing tumors in a mouse model and activated the mitogen-activated protein kinase pathway. Of the uveal melanomas we analyzed, 83% had somatic mutations in GNAQ or GNA11. Constitutive activation of the pathway involving these two genes appears to be a major contributor to the development of uveal melanoma. (Funded by the National Institutes of Health and others.).
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            Generation of Tumor-Infiltrating Lymphocyte Cultures for Use in Adoptive Transfer Therapy for Melanoma Patients

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              Cancer Immunotherapy by Targeting IDO1/TDO and Their Downstream Effectors

              The tryptophan (TRP) to kynurenine (KYN) metabolic pathway is now firmly established as a key regulator of innate and adaptive immunity. A plethora of preclinical models suggests that this immune tolerance pathway – driven by the key and rate-limiting enzymes indoleamine-2,3-dioxygenase and TRP-2,3-dioxygenase – is active in cancer immunity, autoimmunity, infection, transplant rejection, and allergy. Drugs targeting this pathway, specifically indoleamine-2,3-dioxygenase, are already in clinical trials with the aim at reverting cancer-induced immunosuppression. In the past years, there has been an increase in our understanding of the regulation and downstream mediators of TRP metabolism, such as the aryl hydrocarbon receptor as a receptor for KYN and kynurenic acid. This more detailed understanding will expand our opportunities to interfere with the pathway therapeutically on multiple levels. Here, we discuss the perspective of targeting TRP metabolism at these different levels based on reviewing recent insight into the regulation of TRP metabolism and its downstream effectors.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                26 July 2019
                August 2019
                : 11
                : 8
                : 1055
                Affiliations
                [1 ]Medical Oncology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy
                [2 ]Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
                [3 ]Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Policlinico Umberto I, “Sapienza” University, 00162 Rome, Italy
                [4 ]Ophtalmology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy
                [5 ]Pathology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy
                Author notes
                Author information
                https://orcid.org/0000-0002-6442-1707
                https://orcid.org/0000-0001-8263-7248
                https://orcid.org/0000-0002-1132-1761
                https://orcid.org/0000-0003-2996-4404
                Article
                cancers-11-01055
                10.3390/cancers11081055
                6721347
                31357439
                9c013d79-bc68-4d18-8f25-c930000217c3
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 30 June 2019
                : 24 July 2019
                Categories
                Review

                immunotherapy,uveal melanoma,checkpoint inhibitors,pd-l1,nivolumab,pembrolizumab,ipilimumab,ido

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