Immune Profiling of Sarcomas May Lead to New Targeted Therapy Approaches

New evidence is suggesting that extensive immune profiling of sarcomas may unlock likely subtypes susceptible to immunotherapy.

Researchers in Seattle are reporting in the journal Cancer on a detailed overview of the immune microenvironment in soft tissue sarcoma (STS) subtypes. The findings may pave the way for treating certain types of sarcoma with targeted immunotherapies.

The researchers found that undifferentiated pleomorphic sarcoma (UPS), which is a more highly mutated STS subtype, elicited a substantial immune response. The researchers theorized UPS may be well suited to treatment with checkpoint inhibitors based on its immune microenvironment.

“Checkpoint inhibitors have transformed the standard of care for melanoma and lung cancer, but it’s been tough to make headway in developing immunotherapy strategies for sarcomas,” said senior study author Seth Pollack, MD, who is a clinical researcher at Fred Hutchinson Cancer Research Center in Seattle. “Before this study, we had a feeling based on preliminary data that some of the sarcomas would behave very differently based on the immune response, and these findings suggest that we’re on the right track.”

Leiomyosarcoma and pleomorphic sarcomas were the two subtypes that had a greater immune response by nearly all of the measures in the study. The synovial sarcoma (SS) and liposarcoma subsets were found to be less mutated. However, they expressed immunogenic self-antigens. The authors suggest this could open a new avenue of successful immunotherapy in patients with these diagnoses via strategies to improve antigen presentation and T-cell infiltration.

Sarcomas comprise more than 70 different cancers. They can originate anywhere in the body. In the most extensive sarcoma immune profiling to date, Pollack and his colleagues examined tumor samples from 81 patients with types of sarcoma that comprise 75% of the disease (leiomyosarcoma, pleomorphic sarcoma, SS, and liposarcoma).

The researchers identify patterns of immune response in these sarcomas to identify promising targets for therapies. They measured expression of 760 genes that are mainly related to immune function. Pollack said some sarcoma subtypes may be susceptible to checkpoint inhibitor-based strategies. However, sarcomas such as SS and liposarcoma may be more susceptible to other immunotherapeutic strategies, such as adoptive T-cell therapies or therapeutic vaccines.

The study showed that UPS had higher levels of programmed death ligand 1 (PD-L1) and programmed death 1 (PD-1) on immunohistochemistry and had the highest T-cell infiltration based on T-cell receptor sequencing. In addition, the researchers found that T-cell infiltrates in UPS were more oligoclonal compared with SS and liposarcoma. This study was also notable because when the researchers adjusted for STS histologic subtype they found T-cell infiltration and clonality were highly correlated with PD-1 and PD-L1 expression levels.

Pollack said he hopes these findings lead to expanded treatment options for patients with advanced sarcoma. Currently, patients with advanced sarcomas currently have an estimated survival of only 12 to 18 months.