Osteosarcoma and soft-tissue sarcomas with an immune infiltrate express PD-L1: relation to clinical outcome and Th1 pathway activation

Abstract

Immune checkpoint proteins, such as PD-L1 and PD-1, are important in several cancers; however, their role in osteosarcoma (OSA) and soft tissue sarcoma (STS) remains unclear. Our aims were to determine whether subsets of OSA/STS harbor tumor-infiltrating lymphocytes (TILs) and express PD-L1, and how PD-L1 expression is related to clinical outcome. Tissue sections of 25 cases each of untreated undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), liposarcoma (LPS) and 24 of leiomyosarcoma (LMS) were subjected to immunohistochemistry (IHC) for immune cells, PD-L1 and PD-1. RT-qPCR was utilized to quantify levels of PD-L1 mRNA from 33 UPS, 57 MFS and 79 OSA primary-untreated specimens. PD-L1 mRNA levels were tested for their correlation with overall survival in patients presenting without metastases. Transcriptome analysis evaluated biological pathway differences between high and low PD-L1 expressers. A subset of UPS and MFS contained TILs and expressed PD-L1 and PD-1; LMS and LPS did not. PD-L1 levels by IHC and RT-qPCR were positively correlated. PD-L1 over-expression was associated with better survival for UPS and OSA, but not MFS. The Th1 pathway was significantly activated in UPS with high levels of PD-L1 and improved survival. Some sarcoma subtypes harbor TILs and express PD-L1. Patients with UPS and OSA with high levels of PD-L1 had better overall survival than those with low expression levels. Important biological pathways distinguish PD-L1 high and low groups. The stratification of patients with OSA/STS with respect to potential immune therapies may be improved through investigation of the expression of immune cells and checkpoint proteins.

Sarcomas: Immune biomarker expression and checkpoint inhibitor trials

“…CD68+ and CD163+ macrophages are consistently detected across all sarcomas [33,34,38,39,50]. Like other cancer types, sarcomas contain more macrophages than lymphocytes [33,34,51].…”

“…However, increased T cell infiltration among karyotypically complex subtypes is inconsistent across studies, with one publication reporting almost no T cells in leiomyosarcomas [38]. CD8+ infiltration was only found in 57% (8/14) of pleomorphic dermal sarcoma specimens [39], lower than what might be expected in a pleomorphic subtype.…”

“…A majority of studies find CD8+ T cells to be more abundant [11,[32][33][34] relative to FOXP3+ T regulatory cells [32][33][34][35][36]. When divided based on karyotype complexity, copy number-driven sarcomas (DDLPS [11], leiomyosarcoma [35,37], UPS, and myxofibrosarcoma [38]) had higher T cell infiltration than translocation-associated subtypes [11]. In rhabdomyosarcomas, the copy number-and mutationdriven embryonal subtype has more CD3+ and CD8+ T cell infiltration than its translocation-associated counterpart, alveolar rhabdomyosarcoma [36].…”

“…Thus to date, publications on the T cell infiltration in specific histologic subtypes are difficult to compare due to the varying definitions of what constitutes a positive case [29,34] and the different tissue formats and areas examined in the analysis [35,38]. There is a trend for copy-number driven subtypes (DDLPS, MPNST, and UPS) to have positive association between T cell infiltration and prognosis, and translocation-associated subtypes (synovial sarcoma and myxoid liposarcoma) to have mixed results [10].…”

“…Ewing sarcoma [57], chondrosarcoma [64], pediatric [65] and adult [29,36] alveolar and embryonal rhabdomyosarcoma, and synovial sarcoma [29,34,41,58,66] show little to no PD-L1 expression on malignant cells. Studies on DDLPS and pleomorphic liposarcomas [41,64], myxofibrosarcoma [38,41], fibrosarcoma [41], desmoplastic small round cell tumor [29,66], osteosarcoma [38,58,64,67], UPS [38,64], and pleomorphic dermal sarcoma [39] report less than half the cases show PD-L1 expression on the sarcoma cells. In comparison, PD-L1 was expressed on the neoplastic cells in more than half of leiomyosarcoma [35,37,41] and giant cell tumor specimens [58].…”