Abstract
BACKGROUND
Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) or its ligand (PD-L1) have been shown to be effective in treating patients with a variety of cancers. Positive associations between clinical response rates and PD-L1 expression on tumor and immune cells, as well as the presence of tumor infiltrating lymphocytes (TILs) have been found in multiple studies. It is currently unknown whether tumors associated with neurofibromatosis types 1 and 2 (NF1 and NF2) express PD-L1. We hypothesized that NF-associated tumors express PD-L1 and therefore might be amenable to immunotherapy with immune checkpoint inhibitors.
METHODS
We performed immunohistochemistry for PD-L1 (Spring Bioscience, clone SP142 and Cell Signaling Technology, clone E1L3N), CD3, CD20, CD8, and CD68 in 17 NF1-related tumors (11 dermal neurofibromas and 6 plexiform neurofibromas) and 20 NF2-related tumors (10 meningiomas and 10 schwannomas) using archival formalin-fixed paraffin-embedded tissues. Expression of PD-L1 was considered positive in cases with >5% membranous staining of tumor cells, in accordance with previously published biomarker studies.
RESULTS
PD-L1 positive tumor cells with >5% membranous staining using clone SP142 or E1L3N were observed in 100% of plexiform neurofibromas, 82% and 58% of dermal neurofibromas, 70% and 100% of schwannomas, and 40% and 20% of meningiomas, respectively. Sparse to moderate presence of CD68, CD3, or CD8 positive tumor-infiltrating lymphocytes (TILs) was found in 37/37 (100%) of tumor specimens. However, expression of CD20 positive lymphocytes was limited to rare cells detectable in 4/37 (11%) of tumors.
CONCLUSION
Our findings indicate that adaptive resistance to cell-mediated immunity plays a major role in the tumor immune environment of NF1 and NF2-associated tumors. Expression of PD-L1 on tumor cells and presence of TILs suggests that these tumors may be responsive to immune therapy with immune checkpoint inhibitors, which should be explored in clinical trials for NF patients.