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Published on: December 2, 2022
Identification of an Immunogenic Subset of Metastatic Uveal Melanoma
Luke D Rothermel1, Arvind C Sabesan1, Daniel J Stephens1
1Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Purpose:
Uveal melanoma is a rare melanoma variant with no effective therapies once metastases develop. Although durable cancer regression can be achieved in metastatic cutaneous melanoma with immunotherapies that augment naturally existing antitumor T-cell responses, the role of these treatments for metastatic uveal melanoma remains unclear. We sought to define the relative immunogenicity of these two melanoma variants and determine whether endogenous antitumor immune responses exist against uveal melanoma.
Experimental Design:
We surgically procured liver metastases from uveal melanoma (n = 16) and cutaneous melanoma (n = 35) patients and compared the attributes of their respective tumor cell populations and their infiltrating T cells (TIL) using clinical radiology, histopathology, immune assays, and whole-exomic sequencing.
Results:
Despite having common melanocytic lineage, uveal melanoma and cutaneous melanoma metastases differed in their melanin content, tumor differentiation antigen expression, and somatic mutational profile. Immunologic analysis of TIL cultures expanded from these divergent forms of melanoma revealed cutaneous melanoma TIL were predominantly composed of CD8(+) T cells, whereas uveal melanoma TIL were CD4(+) dominant. Reactivity against autologous tumor was significantly greater in cutaneous melanoma TIL compared with uveal melanoma TIL. However, we identified TIL from a subset of uveal melanoma patients which had robust antitumor reactivity comparable in magnitude with cutaneous melanoma TIL. Interestingly, the absence of melanin pigmentation in the parental tumor strongly correlated with the generation of highly reactive uveal melanoma TIL.
Conclusions:
The discovery of this immunogenic group of uveal melanoma metastases should prompt clinical efforts to determine whether patients who harbor these unique tumors can benefit from immunotherapies that exploit endogenous antitumor T-cell populations. Clin Cancer Res; 22(9); 2237-49. ©2015 AACR.
Insights
Uveal melanoma metastases show varied immune responses. Some non-pigmented uveal melanomas generate strong T-cell reactivity, suggesting potential benefit from immunotherapy.
Area of Science:
- Oncology
- Immunology
- Dermatology
Background:
- Uveal melanoma is a rare variant lacking effective therapies for metastatic disease.
- Immunotherapies are successful in metastatic cutaneous melanoma but their role in uveal melanoma is unclear.
Purpose of the Study:
- To compare the immunogenicity of uveal and cutaneous melanoma metastases.
- To determine if endogenous antitumor immune responses exist against uveal melanoma.
Main Methods:
- Surgical procurement of liver metastases from uveal (n=16) and cutaneous (n=35) melanoma patients.
- Comparison of tumor cell populations and tumor-infiltrating lymphocytes (TIL) using radiology, histopathology, immune assays, and whole-exomic sequencing.
Main Results:
- Uveal and cutaneous melanoma metastases differ in melanin content, antigen expression, and mutation profiles.
- Cutaneous melanoma TIL were CD8(+) dominant, while uveal melanoma TIL were CD4(+) dominant.
- While cutaneous melanoma TIL showed greater reactivity, a subset of uveal melanoma TIL exhibited comparable antitumor reactivity, particularly in non-pigmented tumors.
Conclusions:
- A subset of uveal melanoma metastases demonstrates significant immunogenicity.
- The absence of melanin correlates with enhanced TIL reactivity in uveal melanoma.
- Clinical trials are warranted to explore immunotherapy benefits for patients with these immunogenic uveal melanoma tumors.
