Expression and clinical association of programmed cell death-1, programmed death-ligand-1 and CD8+ lymphocytes in primary sarcomas is subtype dependent

Abstract

In order to explore the potential of immune checkpoint blockade in sarcoma, we investigated expression and clinical relevance of programmed cell death-1 (PD-1), programmed death ligand-1 (PD-L1) and CD8 in tumors of 208 sarcoma patients. Primary untreated osteosarcoma (n = 46), Ewing sarcoma (n = 32), alveolar rhabdomyosarcoma (n = 20), embryonal rhabdomyosarcoma (n = 77), synovial sarcoma (n = 22) and desmoplastic small round cell tumors (DSRCT) (n = 11) were examined immunohistochemically. PD-L1 expression was predominantly detected in alveolar and embryonal rhabdomyosarcomas (15% and 16%, respectively). In the alveolar subtype PD-L1 expression was associated with better overall, event-free and metastases-free survival. PD-1 expression on lymphocytes was predominantly seen in synovial sarcomas (18%). High levels of CD8+ lymphocytes were predominantly detected in osteosarcomas (35%) and associated with worse event-free survival in synovial sarcomas. Ewing sarcoma and DSRCTs showed PD-1 on tumor cells instead of on tumor infiltrating lymphocytes. Overall, expression and clinical associations were found to be subtype dependent. For the first time PD-1 expression on Ewing sarcoma (19%) and DSRCT (82%) tumor cells was described.

Immune profiles of desmoplastic small round cell tumor and synovial sarcoma suggest different immunotherapeutic susceptibility upfront compared to relapse specimens

“…[33][34][35] Numerous studies have evaluated the expression of PD-L1 in DSRCT and synovial sarcoma with conflicting results. While some authors reported high levels of PD-L1 in DSRCT tissue 20,36 and in synovial sarcoma, 18 in contrast, and consistent with our findings, two other groups reported very low or no expression of PD-L1 in either tumor type. 19,37 We observed extensive heterogeneity of PD-L1 expression within each tumor type, which might explain the disparate reports.…”

“…Most of these studies show conflicting data on expression levels and clinical outcomes. [17][18][19][20] Whether immunotherapies for DSRCT and synovial sarcoma will be useful is currently unknown. Numerous results from other cancer subtypes suggest that expression of relevant immunologic molecules and intratumoral immune cell infiltrates may be predictive of prognosis and therapeutic response.…”

“…Numerous results from other cancer subtypes suggest that expression of relevant immunologic molecules and intratumoral immune cell infiltrates may be predictive of prognosis and therapeutic response. [20][21][22][23][24][25] In order to explore which immunotherapies may be useful for patients with DSRCT and synovial sarcoma, we sought to describe the immunologic profiles of specimens from each tumor type. We characterized tumoral expression of human leukocyte antigen (HLA)-A/-B/-C and -2-microglobulin (B2M) and calculated a "cytotoxic T-lymphocyte (CTL) target score."…”

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

“…Similarly, osteosarcoma cells express B7-H3 which is correlated with the aggressiveness of the disease and metastatic capacity [85,86]. Program Death Ligand-1 (PDL-1) and PDL-2 were also detectable in all osteosarcoma cases [89][90][91][92][93][94].…”

Prognostic impact of the tumor immune microenvironment in synovial sarcoma

“…However, because these studies comprised a small number of patients with SS, the expression of PD-L1 in SS and its clinical significance remain controversial. [17][18][19][20][21] Understanding how the tumor immune microenvironment relates to the prognosis of patients with SS may clarify the potential for effective immunotherapy for the treatment of SS. However, to the best of our knowledge, the tumor immune microenvironment including TILs, macrophages, and the expression of HLA class I and PD-L1 are not well understood in SS.…”