Immunotherapy for SMARCB1-Deficient Sarcomas: Current Evidence and Future Developments
Carine Ngo1,2, Sophie Postel-Vinay1,3
1ATIP-Avenir Group, Inserm Unit U981, Gustave Roussy, 94800 Villejuif, France.
Abstract:
Mutations in subunits of the SWItch Sucrose Non-Fermentable (SWI/SNF) complex occur in 20% of all human tumors. Among these, the core subunit SMARCB1 is the most frequently mutated, and SMARCB1 loss represents a founder driver event in several malignancies, such as malignant rhabdoid tumors (MRT), epithelioid sarcoma, poorly differentiated chordoma, and renal medullary carcinoma (RMC). Intriguingly, SMARCB1-deficient pediatric MRT and RMC have recently been reported to be immunogenic, despite their very simple genome and low tumor mutational burden. Responses to immune checkpoint inhibitors have further been reported in some SMARCB1-deficient diseases. Here, we will review the preclinical data and clinical data that suggest that immunotherapy, including immune checkpoint inhibitors, may represent a promising therapeutic strategy for SMARCB1-defective tumors. We notably discuss the heterogeneity that exists among the spectrum of malignancies driven by SMARCB1-loss, and highlight challenges that are at stake for developing a personalized immunotherapy for these tumors, notably using molecular profiling of the tumor and of its microenvironment.
Insights
SMARCB1-deficient cancers, though genomically simple, show immunogenicity. This review explores preclinical and clinical data suggesting immunotherapy, including checkpoint inhibitors, may be a viable treatment strategy for these tumors.
Area of Science:
- Oncology
- Immunology
- Cancer Genetics
Background:
- Mutations in the SWItch Sucrose Non-Fermentable (SWI/SNF) complex are found in 20% of human cancers.
- SMARCB1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1) is the most frequently mutated core subunit.
- SMARCB1 loss is a key driver in malignancies like malignant rhabdoid tumors (MRT) and renal medullary carcinoma (RMC).
Purpose of the Study:
- To review preclinical and clinical evidence supporting immunotherapy for SMARCB1-deficient tumors.
- To discuss the potential of immune checkpoint inhibitors as a therapeutic strategy.
- To highlight challenges in developing personalized immunotherapy for these cancers.
Main Methods:
- Review of existing preclinical research.
- Analysis of clinical trial data.
- Discussion of molecular profiling techniques.
Main Results:
- SMARCB1-deficient pediatric MRT and RMC exhibit immunogenicity despite low mutational burden.
- Some SMARCB1-deficient diseases have shown positive responses to immune checkpoint inhibitors.
- Heterogeneity exists across SMARCB1-loss driven malignancies.
Conclusions:
- Immunotherapy, particularly immune checkpoint inhibitors, shows promise for treating SMARCB1-defective tumors.
- Personalized immunotherapy approaches are needed, considering tumor and microenvironment molecular profiles.
- Further research is warranted to overcome challenges in developing tailored treatments.
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