Systemic relapse after
radiotherapy and surgery is the major cause of disease-related mortality in
sarcoma patients. Combining
radiotherapy and
immunotherapy is under investigation as a means to improve response rates. However, the immune contexture of
sarcoma is understudied. Here, we use a retrospective cohort of
sarcoma patients, treated with
neoadjuvant radiotherapy, and TCGA data. We explore therapeutic targets of relevance to
sarcoma, using genomics and multispectral immunohistochemistry to provide insights into the
tumor immune microenvironment across
sarcoma subtypes. Differential gene expression between radioresponsive
myxoid liposarcoma (MLPS) and more radioresistant undifferentiated pleomorphic
sarcoma (UPS) indicated UPS contained higher transcript levels of a number of
immunotherapy targets (CD73/NT5E, CD39/ENTPD1, CD25/IL2RA, and 4-1BB/TNFRSF9). We focused on 4-1BB/TNFRSF9 and other costimulatory molecules. In TCGA data, 4-1BB correlated to an inflamed and exhausted phenotype. OX40/TNFRSF4 and 4-1BB/TNFRSF9 were highly expressed in
sarcoma subtypes versus other
cancers. Despite OX40 and 4-1BB being described as Treg markers, we identified that they delineate distinct
tumor immune profiles. This was true for
sarcoma and other
cancers. While only a limited number of samples could be analyzed, spatial analysis of OX40 expression identified two diverse phenotypes of OX40+ Tregs, one associated with and one independent of
tertiary lymphoid structures (TLSs). Patient stratification is of intense interest for
immunotherapies. We provide data supporting the viewpoint that a cohort of
sarcoma patients, appropriately selected, are promising candidates for
immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification.