Analysis of PD-1, PD-L1, and T-cell infiltration in angiosarcoma pathogenetic subgroups

T Tomassen,I M E Desar,M H S Hillebrandt-Roeffen,U E Flucke,Yvonne M H Versleijen-Jonkers,M E Weidema,C Van Der Horst

doi:10.1007/s12026-021-09259-4

Abstract

Angiosarcoma (AS) is a rare malignancy with a poor prognosis. It can develop spontaneously or due to previous radiotherapy (RT), ultraviolet (UV) radiation, or lymphoedema (Stewart Treves AS). Novel therapeutic approaches are needed, but progress is hindered because of the heterogeneity and rarity of AS. In order to explore the potential of immune checkpoint inhibition (ICI), we investigated the protein expression of programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and CD8 + T cells in 165 AS cases in relation to AS subgroups based on clinical classification and in relation to whole-genome methylation profiling based clusters (A1, A2, B1, B2). High PD-L1 and PD-1 expression were predominantly shown in UV-associated, visceral, and soft tissue AS. RT-associated AS showed predominantly high PD-1 expression. CD8 + T cell infiltration was present in the majority of AS samples. Within the UV-associated AS, two different clusters can be distinguished by DNA methylation profiling. Cases in cluster A1 showed higher PD-1 (p = 0.015), PD-L1 (p = 0.015), and CD8 + T cells (p = 0.008) compared to those in cluster B2, suggesting that these UV-AS tumors are more immunogenic than B2 tumors showing a difference even within one subgroup. In soft tissue AS, combined PD-1 and PD-L1 expression showed a trend toward poor survival (p = 0.051), whereas in UV-associated AS, PD-1 expression correlated with better survival (p = 0.035). In conclusion, we show the presence of PD-1, PD-L1, and CD8 + T cells in the majority of AS but reveal differences between and within AS subgroups, providing prognostic information and indicating to be predictive for ICI.

Highlights

AS is a rare and aggressive vasoformative sarcoma arising at different anatomical sites, including skin, soft tissue, bone, and visceral organs
In order to determine the role of immune checkpoint inhibition (ICI) in AS, it is necessary to examine the expression of programmed death-ligand 1 (PD-L1), programmed cell death 1 (PD-1), and the presence
The expression of PD-1, PD-L1, and CD8 was assessed in 165 AS samples divided over 6 different subgroups

Summary

Introduction

AS is a rare and aggressive vasoformative sarcoma arising at different anatomical sites, including skin, soft tissue, bone, and visceral organs. AS can be clinically classified into primary AS (with unknown etiology) or secondary AS, in. A potential approach for AS treatment is ICI. Tumor cells can upregulate PD-L1 on their membrane to promote immune suppression. Interaction with the receptor programmed cell death 1 (PD-1) on CD8 + T cells renders the T cell inactive, and prevents the killing of tumor cells. ICI with antiPD-1 antibodies can reactivate the cytotoxic function of T cells leading to the subsequent killing of tumor cells [9]. In order to determine the role of ICI in AS, it is necessary to examine the expression of PD-L1, PD-1, and the presence

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