Profiling the tumour immune microenvironment in pleomorphic dermal sarcomas suggests its potential effectiveness for immunotherapy

Abstract

Abstract Background Immune-checkpoint inhibitors have shown high objective response rates and long-lasting clinical benefits in several studies, thus revolutionized cancer treatment. Pleomorphic dermal sarcoma (PDS) is a rare cutaneous tumour with local recurrences and distant metastases occurring up to 20% of the cases. With only limited treatment options in advanced stages, there is a strong rationale to explore novel treatments in PDS. In order to achieve this, the profiling of the immune environment in PDS needs to be first explored. Methods We collected 14 PDS cases that underwent primary surgical resection at University Hospital Cologne. With formalin-fixed paraffin-embedded (FFPE) materials, we performed a comprehensive immune-phenotype analysis using immunohistochemistry and multiplex gene expression analysis, as well as quantitative assessment of immune cells through quantitative image-analysis. Based on these findings and our preliminary studies, two patients with advanced PDS were enrolled in programmed cell death protein 1 (PD-1) inhibitor therapy. Results Eight out of fourteen PDS cases (57%) showed abundance of CD8-positive T-lymphocyte infiltration. Three cases that had above median level of infiltration (hereinafter referred to as CD8-high) displayed high expression levels of immune-related cytokines, immunotherapy response markers, MHC-I expression, and infiltration by PD-L1-, PD-1- and LAG-3-expressing immune cells. The multivariate analysis revealed that CD8-high group highly expressed CD74, LYZ and HLA-B while the CD8-low cases overexpressed CXCL14. In addition, M2 tumor-associated macrophages (TAMs) were localized at the tumor invasion front. Likewise, both patients showed good response to anti-PD-1 therapy in combination with or without radiotherapy and remain in complete remission until now. Conclusion We provide the initial comprehensive immune-phenotype profiling of PDS and two representative cases that were successfully treated with immune-checkpoint inhibitor for the first time. These results will aid in further assessment of PDS cases and formulate the qualification criteria for immunotherapy in individuals presenting this rare skin malignancy. Legal entity responsible for the study University Hospital Cologne. Funding EFRE 2018 (ImmunePredict). Disclosure All authors have declared no conflicts of interest.