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

Purpose The treatment options for metastatic soft tissue sarcomas (STSs) are limited. In most cases, immunotherapy with immune checkpoint inhibitors has not been successful so far. Macrophages dominate the immune landscape of STSs; thus, combinatorial strategies aiming at both tumor-infiltrating lym...

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Published in:Journal of cancer research and clinical oncology 2023-07, Vol.149 (7), p.3789-3801
Main Authors: Ozaniak, Andrej, Smetanova, Jitka, Bartolini, Robin, Rataj, Michal, Capkova, Linda, Hacek, Jaromir, Fialova, Martina, Krupickova, Lenka, Striz, Ilja, Lischke, Robert, Bartunkova, Jirina, Strizova, Zuzana
Format: Article
Language:English
Subjects:
Cancer Research
Cell suspensions
Cytokines
Flow cytometry
Hematology
Immune checkpoint inhibitors
Immunohistochemistry
Immunotherapy
Inflammation
Internal Medicine
Lymphocytes T
Macrophages
Medicine
Medicine & Public Health
Metastases
Metastasis
Monoclonal antibodies
Oncology
Patients
PD-1 protein
Sarcoma
Soft tissue sarcoma
Tumor cells
Tumor microenvironment
Tumor-infiltrating lymphocytes
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Summary:Purpose The treatment options for metastatic soft tissue sarcomas (STSs) are limited. In most cases, immunotherapy with immune checkpoint inhibitors has not been successful so far. Macrophages dominate the immune landscape of STSs; thus, combinatorial strategies aiming at both tumor-infiltrating lymphocytes and macrophages may represent a particularly relevant treatment approach for metastatic or recurrent STSs. Methods In this cohort study, 66 patients who underwent surgery for STSs were enrolled. Tumor cells and tumor-infiltrating immune cells were analyzed using flow cytometry and immunohistochemistry. In cell suspensions obtained from surgical resections, human T cells were activated by superparamagnetic polymer beads and cultured at a concentration of 0.3 × 10 6 /µl in the absence or presence of therapeutic monoclonal antibodies (anti-PD-1, anti-CD47, and anti-PD-1 + anti-CD47). Supernatants from cell suspensions were analyzed using multiplex Luminex cytokine bead-based immunoassays. Results The most profound response to anti-CD47 therapy was observed in an undifferentiated pleiomorphic sarcoma which also displayed high expression of CD47 in the tumor microenvironment. Both anti-PD-1 and anti-CD47 therapies drastically increased the production of pro-inflammatory cytokines in the tumor microenvironment of STSs, but co-administration of both agents did not further increase cytokine secretion. Furthermore, all patient samples treated with a combination of both anti-PD-1 and anti-CD47 antibodies showed a dramatic reduction in cytokine secretion. Conclusion Our findings suggest that anti-PD-1 and anti-CD47 therapies do not enhance each other, and the combined application of anti-PD-1 and anti-CD47 agents in vitro limits rather than potentiates their efficacy.
ISSN:0171-5216
1432-1335
DOI:10.1007/s00432-022-04292-8