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

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.

Immunological and Genomic Analysis Reveals Clinically Relevant Distinctions between Angiosarcoma Subgroups

“…High PD-L1 and PD-1 expression were predominantly shown in UV-associated, visceral, and soft tissue AS. RT-AS showed predominantly high PD-L1 expression [ 45 ]. The value of PD-L1 and PD-1 expression as predictive biomarker of response to immunotherapy is limited as has been discussed extensively before [ 46 ].…”

“…The WHO classification does not define pAS and sAS, nor clinical subgroups [ 47 ]. Clinical subgroups have been defined in various ways previously, with pAS and sAS used most based on tumor etiology [ 8 , 25 , 26 , 45 ]. We used the same classification as we did before [ 8 ].…”

Immunotherapy for Soft Tissue Sarcomas: Anti-PD1/PDL1 and Beyond

“…In light of these results, the Food and Drug Administration (FDA) recently approved atezolizumab for patients with unresectable or metastatic ASPS (9 December 2022). As for angiosarcomas, multiple case reports find a meaningful activity signal [ 24 , 25 , 26 , 27 ], which is partly explained by a mutational profile linked to DNA damage caused by UV exposure, as is the case of face and scalp cutaneous angiosarcomas [ 28 ]. An angiosarcoma cohort was extracted from the trial evaluating dual inhibition by anti-CTLA4 and anti-PD1 in rare tumors (DART) [ 29 ].…”

PD-L1 Expression in Cutaneous Angiosarcomas: A Systematic Review with Meta-Analysis

“…We initially identified 90 studies. After the exclusion of duplicates, irrelevant studies, abstracts, reviews, and other studies not fulfilling the selection criteria, a total of 10 studies reporting on 279 cases were included in the meta-analysis [1,8,10,[18][19][20][21][22][23][24]. The characteristics of the retrieved studies, published between 2016 and 2022, are presented in Table 1.…”