OX40 and 4-1BB delineate distinct immune profiles in sarcoma.
Date
2022-12-31Author
Melake, MJ
Smith, HG
Mansfield, D
Davies, E
Dillon, MT
Wilkins, AC
Patin, EC
Pedersen, M
Buus, R
Melcher, AA
Thway, K
Miah, AB
Zaidi, SH
Hayes, AJ
Fenton, TR
Harrington, KJ
McLaughlin, M
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
CD137
TNFRSF9
TNFSFR4
agonist
immunotherapy
Adult
Humans
Neoplasm Recurrence, Local
Retrospective Studies
Sarcoma
Soft Tissue Neoplasms
T-Lymphocytes, Regulatory
Tumor Microenvironment
Research team
Sarcoma&Melanoma Surgery
Targeted Therapy
Language
eng
Date accepted
2022-03-31
License start date
2022-12-31
Citation
OncoImmunology, 2022, 11 (1), pp. 2066050 -
Publisher
TAYLOR & FRANCIS INC