Systematic analysis of immune profiles in uveal melanoma primary and metastatic tumors

Abstract

Purpose : To date, no systemic therapy, including immunotherapy, exists to improve clinical outcomes in metastatic uveal melanoma (UM) patients. In order to understand the role of immune infiltrates in the genesis, metastasis, and response to treatment for UM, we systematically characterize immune profiles of UM primary and metastatic tumors.

Methods : Important immune markers were analyzed by immunohistochemistry on 27 primary and 31 metastatic tumors from 47 discrete UM patients.

Results : Among primary enucleation cases, most are positive for CD3 (100%), CD8 (96.3%), and CD68 (88.5%). Although 93% and 100% primary UM show positive staining for PD-1 and FOXP3 respectively, the absolute tumor infiltrating PD-1⁺ (mean = 11.0/mm²) and FOXP3⁺ (mean = 15.7/mm²) T cells are considered in low levels. The 29 treatment-naïve metastatic UM all showed positive staining for CD3, CD8, CD68, PD-1, and FOXP3, but all were negative for PD-L1. Compared to primary tumors, treatment-naïve metastatic UM showed significantly higher levels of CD3⁺ (p = 0.0059), CD8⁺ (p = 0.0423), and FOXP3⁺ (p = 0.0028) T lymphocytes. The infiltrating CD68⁺ cells were significantly higher in metastases than primary tumors (p = 0.0424). Similar to primary tumors, the overall PD-1⁺ T cell infiltration was very low in metastases (mean = 21.0/mm2). In our study, 62% of treatment naïve UMs were liver metastases, and 48% of tumors were metastases from lung, soft tissues, and other sites. The levels of all tested immune markers were similar across tissues from different sites. The levels of PD-1⁺ T cells were also positively correlated with CD3⁺ and CD8⁺ infiltrates levels in UM metastases, but only significantly associated with CD8⁺ infiltrates in primary UM. Interestingly, tumor-infiltrating FoxP3⁺ cells showed a significant positive association with the presences of CD8⁺ or CD3⁺ T cells in UM metastases and primary tumors (p < 0.05). In primary UM tumors, FoxP3⁺ cells also showed a significant association with the levels of PD-1⁺ T cells (p < 0.05). The analysis of RNA expression of immune markers of interest in UM by NanoString is ongoing.

Conclusions : Our study provides critical insight into immune profiles of UM primary and metastatic tumors for developing effective immunotherapy options.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.