Comprehensive profiling of tumor samples taken from patients with osteosarcoma showed that multiple factors contribute to the traditionally poor responses observed with immune checkpoint inhibitor treatment in patients with this malignancy, according to new research published by Wu et al in Nature Communications.
Researchers found that poor infiltration of the tumor by immune cells, low activity from available T cells, a lack of immune-stimulating neoantigens, and multiple immune-suppressing pathways all combine to dampen responses to immunotherapy.
Andy Futreal, PhD
Study Background
“This study is important not only because it focuses on a rare cancer, but [because] it sets the groundwork for understanding the multifaceted reasons this cancer doesn’t respond to immunotherapy, despite having certain hallmarks that suggest it would,” said corresponding study author Andy Futreal, PhD, Chair of Genomic Medicine at The University of Texas MD Anderson Cancer Center. “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.”
When diagnosed at early stages, treatment with combination chemotherapy and surgery achieves survival rates of approximately 70% in patients with osteosarcoma; in contrast, metastatic osteosarcoma is associated with survival rates below 30%. These cancers are marked by a large number of genomic alterations and mutations, which often provide greater potential for immunotherapy to be effective, explained Dr. Futreal. However, immune checkpoint inhibitors have so far not proven effective in osteosarcoma clinical trials.
This study sought to characterize the immune profile of osteosarcoma tumor samples. The researchers performed whole-genome, RNA, and T-cell receptor sequencing, immunohistochemistry, and reverse phase protein array profiling on 48 tumor samples from pediatric and adult patients with primary, relapsed, and metastatic osteosarcoma. The majority of the samples were from relapsed (23%) and metastatic (51%) cancers.
Analysis Results
Genomic changes in these samples were similar to those reported previously, and there were few differences between the sample types. In contrast to other cancer types, the genomic changes in these osteosarcomas did not correspond to an increase in the expression of mutated proteins, or neoantigens, which are thought to stimulate an immune response against the tumor.
Photo credit: Getty
The researchers also showed the degree of immune cell infiltration into the tumor was generally lower than that of other tumor types, such as lung cancer and melanoma, where immune checkpoint inhibitors are more effective. Further, T cells in the tumor displayed a low level of activity, shown by low clonality scores.
Gene-expression analysis revealed three distinct classes within the samples studied, corresponding with levels of immune infiltration. “Hot” tumors had the highest degree of immune infiltration, but also had high activity in a number of signaling pathways that suppressed immune activity.
Conversely, “cold” tumors had the lowest levels of immune infiltration, decreased expression of human leukocyte antigen, and a higher number of genes with copy number loss, signaling higher genomic instability.
Interestingly, increased expression of the gene PARP2, which could be targeted by available poly (ADP-ribose) polymerase (PARP) inhibitors, were associated with low immune infiltration in “cold” osteosarcomas, supporting the rationale for studies exploring a combination of PARP inhibitors and checkpoint blockade, explained study coauthor Andrew Livingston, MD, Assistant Professor of Sarcoma Medical Oncology and Pediatrics at MD Anderson.
“By understanding the interplay between tumor genomics and the immune response, we are better equipped to identify [patients with] osteosarcoma who are more likely to benefit from immunotherapy,” said Dr. Livingston. “These findings lay the groundwork for novel clinical trials combining immunotherapy agents with targeted or cell-based therapies to improve outcomes for our patients.”
Disclosure: This research was supported by Triumph Over Kid Cancer Foundation, A Shelter for Cancer Families, WWWW (QuadW) Foundation, the Cancer Prevention & Research Institute of Texas, and The Robert A. Welch Distinguished University Chair in Chemistry. For full disclosures of the study authors, visit nature.com.
