AMSTERDAM – Immune checkpoint inhibitors targeted against programmed death–1 (PD-1) and its ligand (PD-L1) show strong activity against several different tumor types, but unfortunately may have only limited efficacy against soft tissue and bone sarcomas, investigators reported.
“We found that the clinical expression of PD-1, PD-L1, and CD8 is sarcoma subtype dependent,” said Anke van Erp, a PhD candidate in oncology at Radboud University Medical Center in Nijmegen, the Netherlands.
“The introduction of PD-1 antibodies has led to increased interest in the expression of PD-1, PD-L1, and CD8 in a large variety of tumor types, and has shown in several of these tumor types that PD-L1 could be associated with a worse prognosis. In addition, treatment with PD-1 antibodies has shown impressive effects in an increasing number of adult tumors. This makes the exploration of PD-1 blockade in sarcoma of interest,” she said.
Additionally, CD8-positive T cells are of interest because they are critical mediators of adaptive immunity, she noted.
Ms. van Erp and colleagues looked at expression of PD-1, PD-L1, and the presence of CD8-positive cells in formalin-fixed, paraffin-embedded tumor samples from patients with one of six sarcoma subtypes: primary osteosarcoma (48 samples), Ewing sarcoma (32), alveolar rhabdomyosarcoma (28), embryonal rhabdomyosarcoma (78), synovial sarcoma (23), and desmoplastic small round cell tumors (8).
The samples were analyzed by immunohistochemistry for the expression of PD-1, PD-L1, and CD8-positive cells, and expression levels were then correlated with clinical outcomes.
The investigators classified expression of markers on less than 10% of cells in a sample as negative, 10%-50% as positive, and more than 50% as highly positive.
PD-1 was expressed in lymphocytes in 6% of all samples, and in 19% of all tumors. PD-L1 was expressed in 10%, and CD8-positive cells in 46%.
Only 2% of samples expressed both PD-1 and PD-L1, 11% expressed both PD-1 and CD8-positive T cells, 7% had PD-L1 and CD8, and 2% expressed all three markers.
The highest percentages of PD-1 expression were in lymphocytes from synovial sarcoma samples (17%), and the highest levels of PD-1 were seen in alveolar rhabdomyosarcoma samples. However, neither PD-1 nor PD-L1 were detected at significant levels in synovial sarcoma tumor cells, and PD-1 was not detected in tumor cells from alveolar rhabdomyosarcoma.
“These data show that there is a high difference between the different subtypes, and they highlight the need to really look at PD-1 blockade per individual subtype,” Ms. van Erp said.
For all subtypes combined, the OS was significantly better for patients with PD-L1 positive vs. PD-L1–negative tumors out to 25 years of follow-up (P = .028). Similarly OS was better for patients with PD-L1–positive, CD8-positive tumors, compared with tumors negative for both markers (P = .020).
When they looked at individual sarcoma subtypes, however, they saw significant results only for alveolar rhabdomyosarcoma, with PD-L1 positivity vs. negativity associated with better OS and EFS out to more than 10.5 years (P = .007 for both). There was also a trend toward better EFS for tumors positive for both PD-L1 and CD8, but this was not significant.
For Ewing sarcoma, PD-1 was found to be expressed on tumor rather than on lymphocytes in 19% of all samples, and PD-1 expression was found to be associated with worse EFS. PD-1 was also found in tumors of all desmoplastic small round cell tumor samples, but this group was too small to determine significance, Ms. van Erp said.
She acknowledged that the study was limited by the use of tissue microarray sampling rather than examination of the whole tumor and its microenvironment. In addition, no functional assays have been performed to determine the clinical relevance of PD-1 expression for either Ewing sarcoma or desmoplastic small round cell tumor cells.
“In this study, we looked at the primary tumors for these subtypes, and as we know that there can be a difference in the pattern of expression between primary tumors and metastatic tumors in sarcoma subtypes, and as sarcoma patients are in great need for new therapeutic options, it would be very interesting to look at the expression of PD-1. PD-L1, and CD8 in these tumor types in metastatic disease,’ she said.
The study was supported by Radboud University; the Princess Maxima Center for Pediatric Oncology in Utrecht, the Netherlands; and the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London. The authors reported no conflicts of interest.