Immune Checkpoint Markers in Superficial Angiosarcomas: PD-L1, PD-1, CD8, LAG-3, and Tumor-Infiltrating Lymphocytes

Abstract

Cutaneous angiosarcomas may express programmed death ligand-1 (PD-L1) and PD-L1 expression, and the presence of tumor-infiltrating lymphocytes (TILs) correlates with outcome. These observations provide a basis for PD-1/PD-L1 inhibitor therapy. Lymphocyte activation gene 3 (LAG-3) is an inhibitory receptor that interacts with the PD-L1 axis and is considered to be a marker of immune exhaustion. The presence of LAG-3positive lymphocytes in cutaneous angiosarcoma has not been established. We reviewed 10 cases of treatment naive angiosarcoma of skin and superficial soft tissue and assessed for PD-L1 (ZR3) expression, presence of TILs, and expression of CD8, PD1, and LAG-3 by tumor-associated inflammatory cells by immunohistochemistry. All 10 angiosarcomas were positive for PD-L1: 7 with high expression and 3 with low expression. TILs were present in all tumors: brisk in 7 and nonbrisk in 3. CD8 lymphocytes were present in all tumors with a range of 212-1274 cells per square millimeter (mean 557 CD8 cells/mm 2 ). LAG-3-positive lymphocytes were present in 9 of 10 angiosarcomas with a range of 0-728 cells/mm 2 (mean 146 LAG-3 cells cells/mm 2 ). The ratio of LAG-3 lymphocytes to CD8 lymphocytes was 0%-59% (mean 27%). The PD1 cell counts were intermediate between CD8 and LAG3 counts. Cutaneous angiosarcomas frequently express PD-L1, have prominent numbers of CD8 positive, and have smaller numbers of LAG-3-positive and PD-1-positive TILs. Our findings provide further evidence of PD-L1 expression in cutaneous angiosarcoma and the promise for immune checkpoint inhibitor therapy.

PD-L1 expression and CD8 positive lymphocytes in human neoplasms: A tissue microarray study on 11,838 tumor samples

“…For most tumor types, however, the reported frequencies of PD-L1 positivity vary quite considerably. For example, the reported rate of PD-L1 positivity ranges from 0–92% in prostate cancer [ 7 , 8 ], 1.7%–75% in breast cancer [ 9 , 10 ], 5.5–89% in colorectal cancer [ 11 , 12 ], 22–68% in head & neck squamous cell carcinomas [ 13 , 14 ], 5.2–65% in stomach cancer [ 15 , 16 ], 3.9–63% in small cell lung cancer [ 17 , 18 ], 3.1–82% in liver cell carcinomas [ 19 , 20 ], 17–72% in malignant mesothelioma [ 21 , 22 ], 10–92% in malignant melanoma [ 23 , 24 ], 0–100% in chondrosarcoma [ 24 , 25 ], 0–100% in liposarcoma [ 24 , 26 ], and 7–100% in angiosarcoma [ 19 , 27 ]. Technical factors, staining protocols, antibodies used, definitions of thresholds to determine positivity, as well as a possible selection bias with respect to the analyzed tumors have been proposed as causes for these discrepancies.…”

The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers

“…Angiosarcoma (AS) is rare malignant endothelial-cell tumors of vascular or lymphatic origin, and is among the most aggressive subtypes of soft-tissue sarcomas ( 112 , 113 ). In recent years, immunotherapy targeting PD-1/PD-L1 has become a hotspot in the treatment of AS ( 114 , 115 ). A recent study analyzed PD-L1 expression levels in angiosarcomas at different sites in humans and showed that PD-L1 was abnormally expressed in about 66% of the samples ( 116 ).…”

“…Positive PD-L1 expression predicts worse outcome in CAS ( 118 ). Malignant progression and prognosis of CAS are closely associated not only with high expression of PD-L1, but also with the presence of tumor-infiltrating lymphocytes (TILs) ( 114 ). Since high PD-L1 expression is closely related to the progression of CAS, it is also critical to explore upstream regulators that can increase PD-L1 expression.…”

“…In general, PD-1/PD-L1 inhibitory checkpoints suppress T cell receptor-mediated cytotoxicity and CD8 + T cell proliferation by interacting with the ligand PD-L1, thus avoiding the killing effect of the autoimmune system on tumor cells and immune surveillance (8)(9)(10). Immune checkpoint antibodies as promising cancer therapeutic strategies are based on their natural role acting as T cell-activated co-inhibitory receptors.…”

CD8+ T cell exhaustion in anti‐tumour immunity: The new insights for cancer immunotherapy

“…Persisting infections and antigen exposure CD8 + T cells exhaustion has been demonstrated in different kinds of cancer after persistent exposure to antigenic environments [28][29][30]. Moreover, the higher the antigen load and the longer the exposure time to the antigen environment, the more severe the exhaustion of CD8 + T cells [31].…”