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Profiling of Osteosarcomas Uncovers Numerous Mechanisms Blocking Immune Checkpoint Inhibitor Therapy Response

NEW YORK – A number of factors influence the poor response that osteosarcomas have to immune checkpoint inhibitor therapy, a new study profiling the tumors has found.

Osteosarcoma is a rare cancer, with about 900 new cases occurring each year in the US. When it is diagnosed early and treated with a combination of chemotherapy and surgery, survival rates are around 70 percent. But metastatic osteosarcoma is associated with survival rates falling below 30 percent. As osteosarcomas typically harbor a number of genomic mutations, immunotherapies were expected to be an effective therapy for cancer, but that has not been the case.

Researchers led by the University of Texas MD Anderson Cancer Center's Andrew Futreal profiled four dozen osteosarcoma samples to find that the tumors are marked by a lack of neoantigens, poor infiltration of immune cells, low T cell activity, and the enrichment of numerous immune-suppressing pathways — factors that all work to blunt immunotherapy response. But, as they reported in Nature Communications, they also uncovered different classes of osteosarcoma that could respond to particular treatment approaches.

"This study is important not only because it focuses on a rare cancer, but it sets the groundwork for understanding the multifaceted reasons this cancer doesn't respond to immunotherapy, despite having certain hallmarks that suggest it would," Futreal, the senior author of the study, said in a statement. "Understanding those reasons and beginning to pick them apart does begin to give us lines of sight on how to get around the tumor's methods of subverting the immune system." 

The researchers analyzed tumor samples from 48 patients with osteosarcoma, most of whom had relapsed or had metastatic disease. They performed whole-genome, RNA, and T-cell receptor sequencing as well as immunohistochemistry and reverse phase protein array profiling on the samples.

Sequencing analysis uncovered a genomic landscape similar to what had been previously reported in osteosarcoma. But unlike other cancers, genomic alterations in osteosarcoma did not lead to the high expression of neoantigens that would spark an immune response.

While these osteosarcoma samples did exhibit some T-cell infiltration, as determined by staining for CD3-positive T cells, the activity of these T cells was low. In particular, the researchers noted few T-cell clonotypes, suggesting that this low clonal diversity could affect the ability to generate an effective immune response.

As compared to other tumor types — including lung cancer and cutaneous melanoma, which often respond to immune checkpoint blockade, and low-grade gliomas and prostate cancer, which typically don't respond to immunotherapy — osteosarcoma had intermediate immune infiltration scores. Osteosarcomas might not have a high enough immune infiltrate to respond to immune checkpoint inhibitors by themselves, the researchers said.

Additionally, based on gene expression scores, these osteosarcoma samples could be divided into three clusters with increasing levels of immune infiltrate. The "cold" cluster had the lowest level of immune infiltrate and had decreased expression of human leukocyte antigen, a key immune gene, and higher levels of copy number loss. The "hot" cluster, meanwhile, had the highest level of immune infiltration, but also had increased deregulation of signaling pathways like PD1, CTLA4, and interferon gamma that affect immune response. 

In all, the findings indicate there are a number of immune-suppressing mechanisms at work in osteosarcoma.

But the findings also point to ways of circumventing these mechanisms with treatments that might be more effective in patients with these tumor types. For instance, hot cluster tumors might respond to immune checkpoint inhibitors in combination with other immunotherapies or targeted therapies aimed at immunosuppressive genes, while cold cluster tumors might respond to immunotherapy in combination with PARP inhibitors.

"By understanding the interplay between tumor genomics and the immune response, we are better equipped to identify osteosarcoma patients who are more likely to benefit from immunotherapy," co-author Andrew Livingston said in a statement. "These findings lay the groundwork for novel clinical trials combining immunotherapy agents with targeted or cell-based therapies to improve outcomes for our patients."