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Updated: Jul 8, 2026
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Patterns of Response to Immune Checkpoint Inhibitors in Sarcomas With High Tumor Burden and/or Mismatch Repair
Thierry Alcindor1,2, David J Papke2,3, Vinayak Venkataraman1,2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Purpose:
Immune checkpoint inhibitors (ICIs) are frequently used to treat metastatic solid tumors characterized by high tumor mutational burden (TMB) and/or mismatch repair (MMR) deficiency. Most of the literature on their benefit is about carcinomas and melanomas, but little is known about their effects on sarcomas in these settings. In this study, we examined the response pattern to ICI-based therapy in sarcomas with those characteristics.
Methods:
Patients treated in our institution with ICI-based therapy for sarcomas with high TMB and/or MMR deficiency were identified. We analyzed the main outcome of interest, radiologic response to therapy, alongside clinical information including treatment type and duration, histologic diagnosis, germline and somatic MMR deficiency, and ultraviolet A (UVA) mutational signature.
Results:
Among 17 patients identified, TMB ranged from 9 to 151 mut/Mb. Radiologic response was observed in 6 patients. TMB of responding patients ranged from 15-75 mut/Mb. The only responding case of MMR deficiency was seen in the one patient diagnosed with Lynch syndrome. By contrast, none of the five cases of sporadic MMR deficiency responded. The three complete responses were seen in MMR-proficient tumors associated with UVA signature and high TMB.
Conclusion:
Overall, sarcomas with MMR deficiency and/or high TMB show a heterogeneous pattern of responses to ICI-based therapy. Other cellular and molecular factors, such as histology, germline factors, and mutation signatures, likely contribute to the response to ICI treatment in sarcomas.
Insights
Immune checkpoint inhibitors (ICIs) show varied responses in sarcomas with high tumor mutational burden (TMB) or mismatch repair (MMR) deficiency. Factors beyond TMB/MMR status influence ICI therapy effectiveness in these rare cancers.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Immune checkpoint inhibitors (ICIs) are standard for metastatic solid tumors with high tumor mutational burden (TMB) and/or mismatch repair (MMR) deficiency.
- Evidence for ICI efficacy in sarcomas with these biomarkers is limited compared to carcinomas and melanomas.
Purpose of the Study:
- To investigate the response patterns of sarcomas with high TMB and/or MMR deficiency to ICI-based therapy.
- To identify factors associated with treatment response in this patient cohort.
Main Methods:
- Retrospective analysis of 17 sarcoma patients treated with ICIs for high TMB and/or MMR deficiency.
- Evaluation of radiologic response, treatment details, histology, and germline/somatic MMR status.
- Analysis of ultraviolet A (UVA) mutational signatures.
Main Results:
- Radiologic response observed in 6 of 17 patients (TMB 15-75 mut/Mb).
- One patient with Lynch syndrome (germline MMR deficiency) responded; no sporadic MMR-deficient cases responded.
- Three complete responses occurred in MMR-proficient tumors with UVA signature and high TMB.
Conclusions:
- Sarcomas with high TMB and/or MMR deficiency exhibit heterogeneous responses to ICI therapy.
- Histology, germline factors, and specific mutation signatures likely modulate ICI treatment outcomes in sarcomas.
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