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A single local delivery of paclitaxel and nucleic acids via an immunoactive polymer eliminates solid tumors and induces systemic antitumor immunity

ABSTRACT: Despite recent advances in cancer therapy, hard-to-reach, unidentified tumors remain a significant clinical challenge. A promising approach is to treat locatable and accessible tumors locally and stimulate antitumor immunity in situ to exert systemic effects against distant tumors. We hypothesize that a local carrier of immunotherapeutics is critical to the effective activation of in-situ antitumor immunity. Here, we develop a polyethyleneimine derivative (2E’), which activates immune cells and co-delivers hydrophobic immunogenic cell death inducers and immunomodulatory nucleic acids/nucleotides. A single local administration of 2E’ or its combination with paclitaxel and PD-L1 siRNA or cyclic dinucleotide induces strong antitumor immunity, resulting in immediate regression of large established tumors, tumor-free survival, and the resistance to rechallenge and metastasis in different models. This study supports that effective in-situ induction of antitumor immunity can lead to systemic protection from distant and recurrent diseases, where 2E’ plays multiple roles as a simple and versatile carrier of immunotherapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE178971 | GEO | 2022/05/19

REPOSITORIES: GEO

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Project description:Accumulating data support the concept that ionizing radiation therapy (RT) has the potential to convert the tumor into an in situ, individualized vaccine; however this potential is rarely realized by RT alone. Transforming growth factor β (TGFβ) is an immunosuppressive cytokine that is activated by RT and inhibits the antigen-presenting function of dendritic cells and the differentiation of effector CD8+ T cells. Here we tested the hypothesis that TGFβ hinders the ability of RT to promote anti-tumor immunity. Development of tumor-specific immunity was examined in a pre-clinical model of metastatic breast cancer. Mice bearing established 4T1 mouse mammary carcinoma treated with pan-isoform specific TGFβ neutralizing antibody, 1D11, showed significantly improved control of the irradiated tumor and non-irradiated metastases, but no effect in the absence of RT. Notably, whole tumor transcriptional analysis demonstrated the selective upregulation of genes associated with immune-mediated rejection only in tumors of mice treated with RT+TGFβ blockade. Mice treated with RT+TGFβ blockade exhibited cross-priming of CD8+ T cells producing IFNγ in response to three tumor-specific antigens in tumor-draining lymph nodes, which was not evident for single modality treatment. Analysis of the immune infiltrate in mouse tumors showed a significant increase in CD4+ and CD8+ T cells only in mice treated with the combination of RT+TGFβ blockade. Depletion of CD4+ or CD8+ T cells abrogated the therapeutic benefit of RT+TGFβ blockade. These data identify TGFβ as a master inhibitor of the ability of RT to generate an in situ tumor vaccine, which supports testing inhibition of TGFβ during radiotherapy to promote therapeutically effective anti-tumor immunity. We used genome-wide microarray to depict main biological processes responsibles for the therapeutic benefit of the combination ofTGF-beta blockade and local radiotherapy. To gain a more comprehensice protrait of the effects of RT and TGFbeta blockade on gene expressionin tumors, we collected 4T1 tumors 4 days after completion of RT. Three tumors from each group were then subjected to RNA extraction and hybridization on affymetrix array.

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A single local delivery of paclitaxel and nucleic acids via an immunoactive polymer eliminates solid tumors and induces systemic antitumor immunity

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