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Updated: Jun 18, 2025
Isolation and Characterization of Tumor-initiating Cells from Sarcoma Patient-derived Xenografts
Published on: June 13, 2019
Single-Cell Profiling of Sarcomas from Archival Tissue Reveals Programs Associated with Resistance to Immune
Karan Luthria1, Parin Shah1,2, Blake Caldwell1
1Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
Purpose:
Sarcoma encompasses a diverse group of cancers that are typically resistant to current therapies, including immune checkpoint blockade (ICB), and underlying mechanisms are poorly understood. The contexture of sarcomas limits generation of high-quality data using cutting-edge molecular profiling methods, such as single-cell RNA-sequencing, thus hampering progress in understanding these understudied cancers.
Experimental Design:
Here, we demonstrate feasibility of producing multimodal single-cell genomics and whole-genome sequencing data from frozen tissues, profiling 75,716 cell transcriptomes of five undifferentiated pleomorphic sarcoma and three intimal sarcoma samples, including paired specimens from two patients treated with ICB.
Results:
We find that genomic diversity decreases in patients with response to ICB, and, in unbiased analyses, identify cancer cell programs associated with therapy resistance. Although interactions of tumor-infiltrating T lymphocytes within the tumor ecosystem increase in ICB responders, clonal expansion of CD8+ T cells alone was insufficient to predict drug responses.
Conclusions:
This study provides a framework for studying rare tumors and identifies salient and treatment-associated cancer cell intrinsic and tumor microenvironmental features in sarcomas.
Insights
This study reveals that genomic diversity in sarcoma decreases with successful immune checkpoint blockade (ICB) therapy. Understanding these genomic and microenvironmental features is key to improving sarcoma treatment outcomes.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Sarcomas are a group of cancers resistant to therapies like immune checkpoint blockade (ICB).
- Limited high-quality molecular data from sarcomas hinders understanding of resistance mechanisms.
Purpose of the Study:
- To demonstrate the feasibility of generating multimodal single-cell genomics data from frozen sarcoma tissues.
- To identify cancer cell intrinsic and tumor microenvironmental features associated with ICB response and resistance.
Main Methods:
- Profiling 75,716 cell transcriptomes from five undifferentiated pleomorphic sarcoma and three intimal sarcoma samples.
- Utilizing multimodal single-cell genomics and whole-genome sequencing on frozen tissues.
- Analyzing paired tumor specimens from patients treated with ICB.
Main Results:
- Genomic diversity decreased in patients responding to ICB.
- Identified cancer cell programs associated with therapy resistance.
- Increased T lymphocyte interactions in ICB responders, but CD8+ T cell expansion alone did not predict response.
Conclusions:
- Established a framework for studying rare tumors like sarcomas.
- Identified key cancer cell and tumor microenvironment features linked to sarcoma treatment response.
