Expression of immune checkpoint receptors Indoleamine 2,3-dioxygenase and T cell Ig and ITIM domain in metastatic versus nonmetastatic choroidal melanoma

• Type of Material: Article
• Authors: Gustav Stålhammar, St. Ögon Sjukhus; Stefan Seregard, St. Ögon Sjukhus; Hans Grossniklaus, Emory University
• Language: English
• Date: 2019-06-01
• Publisher: Wiley Open Access
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/cam4.2167
• Title of Journal or Parent Work: Cancer Medicine
• ISSN: 2045-7634
• Volume: 8
• Issue: 6
• Start Page: 2784
• End Page: 2792
• Grant/Funding Information: This research was partially supported by grants to Gustav Stålhammar from St. Erik Eye Hospital, the St. Erik Research Foundation (S:t Eriks Ögonforskningsstiftelse), the Swedish Ophthalmological Society, Cronqvists stiftelse (Cronqvist foundation), the Swedish Eye Foundation (ögonfonden) and Karolinska Institutet (Karolinska Institutets stiftelsemedel för ögonforskning), and partially by the National Institutes of Health/National Cancer Institute (R01CA176001 and P30EY06360) to Hans E. Grossniklaus.
• Keywords: digital image analysis; immunohistochemistry; Uveal melanoma; TIGIT; IDO; immune checkpoints
• Research Categories: Health Sciences, Opthamology; Biology, Cell; Health Sciences, Oncology

Abstract

Background: Survival in metastasized cutaneous melanoma (CM) has been improved with the advent of inhibitors of immune checkpoints CTLA4 and PD-1. In contrast, the response rate for inhibition of these checkpoints in uveal melanoma (UM) is very low. Other checkpoints including IDO and TIGIT may be targetable. Methods: Sections from 6 patients with UM, who had undergone primary enucleation 1978—1995 and 6 paired liver metastases were stained immunohistochemically (SOX10, Melan-A, IDO, TIGIT, and CD8). Four tumors from patients who did not develop metastasis during a mean follow-up of 19 years, and 5 samples each of normal choroidal and liver tissue were included for comparison. The number of cells/mm2 expressing IDO, TIGIT and CD8 was counted with manual and digital image analysis methods. Retrospective data on patient and tumor characteristics was reviewed. Results: The number of TIGIT positive cells was significantly higher in primary tumors from patients who eventually developed metastases (mean 4695 cells/mm2) than from patients who didn't (mean 1342 cells/mm2, P < 0.01) and paired metastases (463 cells/mm2, P < 0.01). The number of IDO positive cells was not significantly higher in metastatic tumors (P = 0.079), but the number of IDO and TIGIT positive cells/mm2 correlated in both hot spots (R2 = 0.24, P < 0.01) and full tumor sections (R2 = 0.35, P < 0.01). Conclusion: The expression of immune checkpoint receptor TIGIT is increased in primary uveal melanomas that seed metastases, and correlates with the expression of checkpoint receptor IDO. Both may be future targets for therapy.