Rewiring innate and adaptive immunity with TLR9 agonist to treat osteosarcoma

Journal of Experimental & Clinical Cancer Research

Research

Adriana Salvaggio¹  Chiara Ratti¹  Claudia Chiodoni¹  Caterina Cascini¹  Laura Botti¹  Beatrice Parma¹  Mario P. Colombo¹  Valeria Cancila²  Claudio Tripodo³  Cristina Meazza⁴ 

[1] Department of Experimental Oncology, Molecular Immunology Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via Amadeo 42, 20133, Milan, Italy;Department of Health Science, Tumor Immunology Unit, University of Palermo School of Medicine, Palermo, Italy;Department of Health Science, Tumor Immunology Unit, University of Palermo School of Medicine, Palermo, Italy;IFOM, FIRC Institute of Molecular Oncology, Milan, Italy;Pediatric Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy;

关键词: Osteosarcoma;    Immunomodulation;    Lymphocyte activation;    Macrophages;    TLR9;    Mouse models;   

DOI  :  10.1186/s13046-023-02731-z

 received in 2023-03-07, accepted in 2023-06-07,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundOsteosarcoma (OS) is the most common primary bone tumor in children and adolescent. Surgery and multidrug chemotherapy are the standard of treatment achieving 60–70% of event-free survival for localized disease at diagnosis. However, for metastatic disease, the prognosis is dismal. Exploiting immune system activation in the setting of such unfavorable mesenchymal tumors represents a new therapeutic challenge.MethodsIn immune competent OS mouse models bearing two contralateral lesions, we tested the efficacy of intralesional administration of a TLR9 agonist against the treated and not treated contralateral lesion evaluating abscopal effect. Multiparametric flow cytometry was used to evaluate changes of the tumor immune microenviroment. Experiments in immune-deficient mice allowed the investigation of the role of adaptive T cells in TLR9 agonist effects, while T cell receptor sequencing was used to assess the expansion of specific T cell clones.ResultsTLR9 agonist strongly impaired the growth of locally-treated tumors and its therapeutic effect also extended to the contralateral, untreated lesion. Multiparametric flow cytometry showed conspicuous changes in the immune landscape of the OS immune microenvironment upon TLR9 engagement, involving a reduction in M2-like macrophages, paralleled by increased infiltration of dendritic cells and activated CD8 T cells in both lesions. Remarkably, CD8 T cells were needed for the induction of the abscopal effect, whereas they were not strictly necessary for halting the growth of the treated lesion. T cell receptor (TCR) sequencing of tumor infiltrating CD8 T cells showed the expansion of specific TCR clones in the treated tumors and, remarkably, their selected representation in the contralateral untreated lesions, providing the first evidence of the rewiring of tumor-associated T cell clonal architectures.ConclusionsOverall these data indicate that the TLR9 agonist acts as an in situ anti-tumor vaccine, activating an innate immune response sufficient to suppress local tumor growth while inducing a systemic adaptive immunity with selective expansion of CD8 T cell clones, which are needed for the abscopal effect.Graphical Abstract

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

40517_2023_252_Article_IEq140.gif

Fig. 4

40517_2023_252_Article_IEq132.gif

40517_2023_252_Article_IEq112.gif

40517_2023_252_Article_IEq103.gif

Fig. 1

40517_2023_252_Article_IEq74.gif

40517_2023_252_Article_IEq55.gif

40517_2023_252_Article_IEq41.gif

Fig. 3

Fig. 5

Fig. 3

40517_2023_259_Article_IEq79.gif