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.
Highlights
Sarcomas represent a very heterogeneous group of rare soft tissue and bone cancers, which comprise more than 100 subtypes, and arise in all age groups, making it difficult to treat
Rhabdoid Tumor, ATRT) and extrarenal sites (Extra-Renal Rhabdoid Tumor, ERRT). They classified in two clinicopathological subtypes: (i) the distal type, which prepresent a remarkably simple genome and are uniquely characterized by a biallelic deletion dominantly arises from the superficial distal sites and is most prevalent in adolescents of SMARCB1 in more than 95% of cases [25–27]
Converging recent data support that SMARCB1 loss favors anti-tumor immunogenicity, at least in certain subtypes of SMARCB1-deficient sarcomas and carcinomas
Summary
Sarcomas represent a very heterogeneous group of rare soft tissue and bone cancers, which comprise more than 100 subtypes, and arise in all age groups, making it difficult to treat. Other classifiers have emerged, notably based on DNA methylation profiles [3], or on digital pathology associated with artificial intelligence/deep learning analyses, which all represents valuable additional tools for sarcoma classification [4]. Sucrose Non-Fermentable (mSWI/SNF) chromatin remodeling complex have been found in 20% of human cancers and are frequent in certain sarcoma subtypes [5]. Development of immunotherapy has encountered challenges due to the rarity and high heterogeneity of the disease. Recent scientific advances and clinical results have enabled the identification of sarcoma subgroups that may most benefit from ICI, together with potential predictive biomarkers of efficacy. MSWI/SNF defects emerged recently as a putative promising predictive biomarker of sensitivity to ICI [9,10]. This review will discuss the current evidence for using immunotherapy in SMARCB1deficient sarcoma
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