Deconvolution of sarcoma methylomes reveals varying degrees of immune cell infiltrates with association to genomic aberrations

Simon, Malte; Mughal, Sadaf S.; Horak, Peter; Uhrig, Sebastian; Buchloh, Jonas; Aybey, Bogac; Glimm, Hanno; Fröhling, Stefan; Brors, Benedikt; Imbusch, Charles D.

doi:10.1186/s12967-021-02858-7

Cited by 6 publications

(8 citation statements)

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“…A few studies focused on TME in STS, based on gene expression profiling. This TME is heterogeneous and correlates to histological subtype, even if TAMs and CD8+ T cells are generally the most represented cells ( 76 – 78 ).…”

Section: The Tumor Microenvironment Of Soft-tissue Sarcomasmentioning

confidence: 99%

Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review

et al. 2021

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Anti-PD-(L)1 therapies yield a disappointing response rate of 15% across soft-tissue sarcomas, even if some subtypes benefit more than others. The proportions of TAMs and TILs in their tumor microenvironment are variable, and this heterogeneity correlates to histotype. Tumors with a richer CD8+ T cell, M1 macrophage, and CD20+ cells infiltrate have a better prognosis than those infiltrated by M0/M2 macrophages and a high immune checkpoint protein expression. PD-L1 and CD8+ infiltrate seem correlated to response to immune checkpoint inhibitors (ICI), but tertiary lymphoid structures have the best predictive value and have been validated prospectively. Trials for combination therapies are ongoing and focus on the association of ICI with chemotherapy, achieving encouraging results especially with pembrolizumab and doxorubicin at an early stage, or ICI with antiangiogenics. A synergy with oncolytic viruses is seen and intratumoral talimogene laherpavec yields an impressive 35% ORR when associated to pembrolizumab. Adoptive cellular therapies are also of great interest in tumors with a high expression of cancer-testis antigens (CTA), such as synovial sarcomas or myxoid round cell liposarcomas with an ORR ranging from 20 to 50%. It seems crucial to adapt the design of clinical trials to histology. Leiomyosarcomas are characterized by complex genomics but are poorly infiltrated by immune cells and do not benefit from ICI. They should be tested with PIK3CA/AKT inhibition, IDO blockade, or treatments aiming at increasing antigenicity (radiotherapy, PARP inhibitors). DDLPS are more infiltrated and have higher PD-L1 expression, but responses to ICI remain variable across clinical studies. Combinations with MDM2 antagonists or CDK4/6 inhibitors may improve responses for DDLPS. UPS harbor the highest copy number alterations (CNA) and mutation rates, with a rich immune infiltrate containing TLS. They have a promising 15-40% ORR to ICI. Trials for ICB should focus on immune-high UPS. Association of ICI with FGFR inhibitors warrants further exploration in the immune-low group of UPS. Finally translocation-related sarcomas are heterogeneous, and although synovial sarcomas a poorly infiltrated and have a poor response rate to ICI, ASPS largely benefit from ICB monotherapy or its association with antiangiogenics agents. Targeting specific neoantigens through vaccine or adoptive cellular therapies is probably the most promising approach in synovial sarcomas.

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Section: The Tumor Microenvironment Of Soft-tissue Sarcomasmentioning

confidence: 99%

Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review

et al. 2021

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“…Interestingly, it has been frequently shown that TIL levels in DDLPS also range among the highest compared to other STS subtypes [ 86 , 90 , 91 ], which also applies to the percentage of TIL-positive tumors [ 92 ]. Moreover, about 40% of DDLPS represent tumors with high T cell infiltration termed immune-hot [ 93 ].…”

Section: Lps-infiltrating Immune Cell Subsets and Their Clinical Sign...mentioning

confidence: 99%

The Immune Contexture of Liposarcoma and Its Clinical Implications

Resag

Toffanin

Benešová

et al. 2022

Cancers

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Liposarcomas (LPS) are the most frequent malignancies in the soft tissue sarcoma family and consist of five distinctive histological subtypes, termed well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. They display variations in genetic alterations, clinical behavior, and prognostic course. While accumulating evidence implicates a crucial role of the tumor immune contexture in shaping the response to anticancer treatments, the immunological landscape of LPS is highly variable across different subtypes. Thus, DDLPS is characterized by a higher abundance of infiltrating T cells, yet the opposite was reported for MLPS. Interestingly, a recent study indicated that the frequency of pre-existing T cells in soft tissue sarcomas has a predictive value for immune checkpoint inhibitor (CPI) therapy. Additionally, B cells and tertiary lymphoid structures were identified as potential biomarkers for the clinical outcome of LPS patients and response to CPI therapy. Furthermore, it was demonstrated that macrophages, predominantly of M2 polarization, are frequently associated with poor prognosis. An improved understanding of the complex LPS immune contexture enables the design and refinement of novel immunotherapeutic approaches. Here, we summarize recent studies focusing on the clinicopathological, genetic, and immunological determinants of LPS.

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“…Following publication of the original article [ 1 ], the authors identified an error in the affiliation 2 for the authors. The incorrect and correct affiliation information is shown below.…”

Section: Correction To: J Transl Med (2021) 19:204 Https://...mentioning

confidence: 99%

“…The incorrect and correct affiliation information is shown below. The author group has been updated above and the original article [ 1 ] has been corrected. Also, affiliation 2 should have been removed as one of the affiliations of the author Benedikt Brors:…”

Section: Correction To: J Transl Med (2021) 19:204 Https://...mentioning

confidence: 99%

Correction to: Deconvolution of sarcoma methylomes reveals varying degrees of immune cell infiltrates with association to genomic aberrations

et al. 2022

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Deconvolution of sarcoma methylomes reveals varying degrees of immune cell infiltrates with association to genomic aberrations

Cited by 6 publications

References 64 publications

Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review

Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review

The Immune Contexture of Liposarcoma and Its Clinical Implications

Correction to: Deconvolution of sarcoma methylomes reveals varying degrees of immune cell infiltrates with association to genomic aberrations

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