The Programmed Death Pathway in Ocular Adnexal Sebaceous Carcinoma

The Programmed Death Pathway in Ocular Adnexal Sebaceous Carcinoma: Purpose:

Sebaceous carcinoma can be highly malignant and difficult to treat. Surgical excision followed by periocular reconstruction is the primary method of treatment. In aggressive cases, radiation, topical chemotherapy, and systemic chemotherapy have been explored as adjuvant therapy. Immunotherapy, through immune checkpoint inhibitors, has proven to have significant antitumor effect in many cancer types, including melanoma, non-small cell lung cancer, renal cell carcinoma, and cutaneous squamous cell carcinoma. Little is known about endogenous immune response directed against sebaceous carcinoma. In this study, we aim to characterize the expression pattern of PD-1 and its ligands PD-L1 and PD-L2 in both sebaceous carcinoma and in infiltrating immune cells to explore the potential use of checkpoint blockade as therapy.

Methods:

We performed a retrospective chart and histology review of patients with sebaceous carcinoma between 1990 and 2017 at the University of Wisconsin. Tissue microarrays were made from paraffin blocks. Immunohistochemistry was performed for evaluation of tumor and immune cell infiltration for expression of PD-1, PD-L1, and PD-L2. Tumor or infiltrating immune cells were considered positive if ≥5% of cells had membranous (cell surface) expression.

Results:

Twenty-eight patients were included. PD-L1 and PD-1 were not significantly expressed on tumor cells; however, PD-L1 and PD-1 were expressed on infiltrating immune cells in 46% and 25% of patients, respectively. In contrast, PD-L2 demonstrated positive expression on tumor cells in 46% of the cases along with positive expression on infiltrating immune cells in 38% of the cases.

Conclusions:

Sebaceous carcinoma currently has few effective adjuvant treatment options. The expression of PD-1, PD-L1, and PD-L2 on infiltrating immune cells and PD-L2 on tumor cells restrains T-cells from full activation and proliferation, therefore limiting the antitumor effect of T-cells, tipping the balance toward unopposed tumor progression. Consequently, PD-1 or PD-L1 inhibitors may have a role in sebaceous carcinoma treatment. Given the prevalence of PD-L2 expression in sebaceous carcinoma and the lack of PD-L2 blockade therapy available, PD-1 blockade may provide benefit over PD-L1 inhibitors. PD-1 blockade in combination with current methods may be a viable therapeutic option for patients with sebaceous carcinoma and deserves further study.

Accepted for publication August 4, 2019.

Supported by NIH Core Grant P30 EY016665; an Unrestricted Grant from Research to Prevent Blindness, Inc. to the UW Department of Ophthalmology and Visual Science, and Richard K. Dortzbach Professorship of Ophthalmic Facial Plastic Surgery. Dr. Mark Lucarelli receives support from the Richard K. Dortzbach Professorship of Ophthalmic Facial Plastics Surgery.

The authors have no financial or conflicts of interest to disclose.

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Presented at Meetings: American Society of Ophthalmic Plastic and Reconstructive Surgery on October 26, 2018, Chicago, IL.

All listed authors contributed to the design or acquisition of data, analysis or interpretation of data and contributed to drafting or critically revising the article for important intellectual content and final approval of the version to be published.

Address correspondence and reprint requests to Randy C. Bowen, MD, MS, Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53705. E-mail: rcbowenMD@gmail.com

© 2019 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.