A novel anti-CD47-targeted blockade promotes immune activation in human soft tissue sarcoma but does not potentiate anti-PD-1 blockade

Ozaniak, Andrej; Smetanova, Jitka; Bartolini, Robin; Rataj, Michal; Čapková, Linda; Háček, Jaromír; Fialová, Markéta; Krupickova, Lenka; Střı́ž, Ilja; Lischke, Robert; Bartůňková, Jiřina; Střížová, Zuzana

doi:10.1007/s00432-022-04292-8

Cited by 13 publications

(15 citation statements)

References 60 publications

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“…Biomolecular studies are needed to confirm the hypothesis that macrophages in the marginal area play an important role in progression of sarcoma. Similar to other studies, the results of the present study suggest that there are therapeutic benefits in targeting macrophages as a treatment for sarcoma 36 .…”

Section: Discussionsupporting

confidence: 92%

Macrophage numbers in the marginal area of sarcomas predict clinical prognosis

Umakoshi

Nakamura

Tsuchie

et al. 2023

Sci Rep

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Even when treated comprehensively by surgery, chemotherapy, and radiotherapy, soft-tissue sarcoma has an unfavorable outcome. Because soft-tissue sarcoma is rare, it is the subject of fewer clinicopathological studies, which are important for clarifying pathophysiology. Here, we examined tumor-associated macrophages in the intratumoral and marginal areas of sarcomas to increase our knowledge about the pathophysiology. Seventy-five sarcoma specimens (not limited to a single histological type), resected at our institution, were collected, and the number of CD68-, CD163-, and CD204-positive macrophages in the intratumoral and marginal areas was counted. We then performed statistical analysis to examine links between macrophage numbers, clinical factors, and outcomes. A high number of macrophages positive for all markers in both areas was associated with worse disease-free survival (DFS). Next, we divided cases according to the FNCLCC classification (Grade 1 and Grades 2/3). In the Grade 1 group, there was no significant association between macrophage number and DFS. However, in the Grade 2/3 group, high numbers of CD163- and CD204-positive macrophages in the marginal area were associated with poor DFS. By contrast, there was no significant difference between the groups with respect to high or low numbers of CD68-, CD163-, or CD204-positive macrophages in the intratumoral area. Multivariate analysis identified the number of CD163- and CD204-positive macrophages in the marginal area as an independent prognostic factor. Macrophage numbers in the marginal area of soft-tissue sarcoma may better reflect clinical behavior.

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Section: Discussionsupporting

confidence: 92%

Macrophage numbers in the marginal area of sarcomas predict clinical prognosis

Umakoshi

Nakamura

Tsuchie

et al. 2023

Sci Rep

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“…The dissociated tissue was then incubated with 5 mL of RPMI-1640 medium (Gibco™ RPMI 1640 Medium, Thermo Fisher Scientific) at room temperature and enzymatically processed according to a previously published protocol [4, 34]. The cell suspension was filtered through a 100-μm cell strainer, and all debris/cell clumps were removed.…”

Section: Methodsmentioning

confidence: 99%

“…Surgical resection is the first-line treatment for resectable tumors [3]. However, approximately 50% of patients with high-grade STSs die of metastatic disease [4]. Systemic treatments for advanced and/or metastatic STSs rarely improve overall survival [5].…”

Section: Introductionmentioning

confidence: 99%

Oncostatin M and Nivolumab Affect the Cytotoxic T-Cell Proportions and the Susceptibility to TRAIL-Induced Death in Non-Leukocyte Cell Subpopulations in Soft Tissue Sarcomas

Toffanin¹,

Ozaniak²,

Bartolini³

et al. 2023

Pharmacology

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Introduction: Soft tissue sarcomas (STSs) are malignant tumors arising from mesenchymal tissues. Patients with advanced and metastatic STSs have low overall survival rates and relatively limited treatment options. Oncostatin M (OSM) is a pleiotropic cytokine that was shown to carry both pro- and anti-tumorigenic properties in various cancer types. However, the role of OSM in STSs has not yet been elucidated. Moreover, the potential additive effects of combining OSM and anti-PD-1 therapy have not been carried out so far. Methods: The aim of this study was to determine the effects of in vitro OSM administration on liposarcoma, leiomyosarcoma, and myxofibrosarcoma immune cells isolated from peripheral blood and tumor tissues and the potential cooperative nature of OSM and nivolumab in treating these STSs. We designed a cohort study to explore novel histology-driven therapies in our target STSs. The immune cells were isolated from the peripheral blood and tumors of patients with STS, and the proportions and phenotypes of immune cells were evaluated with flow cytometry after cultivation with therapeutic monoclonal antibodies. Results: The proportion of peripheral CD45+ cells was not affected by OSM but was significantly increased by nivolumab, whereas both treatments had an effect on CD8+ T cells. In tumor tissues, CD8+ T cell and CD45‒ TRAIL+ cell cultures were boosted by nivolumab and significantly enriched by OSM. Our data suggest that OSM may play a role in the treatment of leiomyosarcoma, myxofibrosarcoma, and liposarcoma. Conclusion: In conclusion, the biological efficacy of OSM is reflected in the tumor microenvironment rather than in the peripheral blood of the patients in our cohort, and nivolumab could potentiate its mechanism of action in selected cases. Nevertheless, more histotype-tailored studies are needed to fully understand the functions of OSM in STSs.

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“…Among STS, CD47 expression appears bimodal, with the highest protein expression level observed in chordoma, angiosarcoma, and pleomorphic liposarcoma; CD47-expressing tumors are associated with worse OS than are CD47-negative tumors [ 169 ]. Anti-CD47 therapy has yielded promising results in early-phase clinical trials among patients with both solid and liquid tumors [ 170 , 171 ], and in vitro experimentation suggests that anti-CD47 therapy induces the expression of proinflammatory cytokines IL2, TNFα, and IFNγ in STS [ 172 ]. As such, anti-CD47 therapy may represent a promising therapeutic option for LMS patients, particularly given the macrophage-rich tumor microenvironment, and warrants further investigation.…”

Section: Immune Landscape Of Lmsmentioning

confidence: 99%

Targeting the Molecular and Immunologic Features of Leiomyosarcoma

Cope

Traweek

Lazcano

et al. 2023

Cancers

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Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. LMS often demonstrates aggressive tumor biology, with a higher risk of developing distant metastatic disease than most sarcoma histologic types. The prognosis is poor, particularly in patients with uterine disease, and there is a need for the development of more effective therapies. Genetically, LMS is karyotypically complex and characterized by a low tumor mutational burden, with frequent alterations in TP53, RB1, PTEN, and DNA damage response pathways that may contribute to resistance against immune-checkpoint blockade monotherapy. The LMS immune microenvironment is highly infiltrated with tumor-associated macrophages and tumor-infiltrating lymphocytes, which may represent promising biomarkers. This review provides an overview of the clinical and pathologic behavior of both soft tissue and uterine LMS and summarizes the genomic and immune characteristics of these tumors and how they may provide opportunities for the development of biomarker-based immune therapies.

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A novel anti-CD47-targeted blockade promotes immune activation in human soft tissue sarcoma but does not potentiate anti-PD-1 blockade

Abstract: A novel anti-CD47-targeted blockade promotes immune activation in human soft tissue sarcoma but does not potentiate anti-PD-1 blockade

Cited by 13 publications

References 60 publications

Macrophage numbers in the marginal area of sarcomas predict clinical prognosis

Macrophage numbers in the marginal area of sarcomas predict clinical prognosis

Oncostatin M and Nivolumab Affect the Cytotoxic T-Cell Proportions and the Susceptibility to TRAIL-Induced Death in Non-Leukocyte Cell Subpopulations in Soft Tissue Sarcomas

Targeting the Molecular and Immunologic Features of Leiomyosarcoma

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