Keywords
Sarcoma; Undifferentiated pleomorphic sarcoma; Immunotherapy; CD276; CSF1R; PD-L1; PD-L2; TGFB1; OX40; Epithelial to mesenchymal transition; Tumor infiltrating macrophages; Inflamed; Non-inflamed
Abstract
Introduction: In sarcoma, no attention has been given to targets beyond the PD-1/PD-L1 axis. We profiled the immune microenvironment of sarcoma with a focus on Undifferentiated Pleomorphic Sarcoma (UPS), to identify novel immunotherapy targets.
Materials and Methods: Microsatellite instability, Tumor Mutation Burden (TMB), PD-L1 IHC and RNA-seq of 395 immune-focused transcripts were performed in 63 sarcomas, including 21 UPS. The expression of each transcript in the 63 sarcomas and a 1295 non-sarcoma solid tumor population was ranked against 167 cases of a diverse solid tumor reference population. The sarcoma (UPS and non-UPS) expression ranks were compared against the expression ranks of the 1295 non-sarcoma tumors using the Wilcoxon Rank-Sum test.
Results: Thirty eight percent and 19% UPS and non-UPS, respectively, were PD-L1 positive by IHC. Microsatellite instability and high TMB were not seen in any specimen. Compared to the 1295 non-sarcoma tumors, the immune therapy targets CD276 (B7-H3) and TGFB1 were significantly over expressed in UPS and non-UPS. The epithelial to mesenchymal transition-related SNAI2, TWIST, and ZEB1 were over expressed in both groups. UPS over expressed PD-L2, CSF1R, CD68 and CD163, while non-UPS over expressed OX40. “Inflamed” sarcomas tended to contain abundant CD8 transcripts and were more frequently PD-L1 IHC positive while “cold” sarcomas tended to be metastatic and non-UPS.
Discussion: A substantial subset of UPS and non-UPS are positive for PD-L1 IHC. The high expression of PD-L2 in UPS suggests that the PD-1/PD-L1 axis may be important in UPS. CD276 (B7-H3) and TGFB1 are other possible immunotherapy targets in sarcoma. CSF1R and OX40 are possible immunotherapy targets in UPS and non-UPS respectively. Myeloid suppression may be an immunosuppressive mechanism in UPS. Epithelial to mesenchymal transition is a possible mechanism of immune suppression in both UPS and non-UPS. Sarcomas can be categorized in “inflamed” and “cold” categories which associate with histological category, metastatic, and PD-L1 status.
Citation
Papanicolau-Sengos A, De Pietro P, Pabla S, Lenzo F, Conroy J, Burgher B, et al. RNA-Expression Profiling Reveals Immunotherapy Targets in Sarcoma. SM J Sarcoma Res. 2018; 2(1): 1011.