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A Senescent Tumor Cell-Derived Nanovesicle Directly Primes Splenic T cells to Potentiate Radiotherapy

ABSTRACT: Senescent tumor cells (STCs) play a crucial role for radiotherapy-induced immunosuppressive tumor microenvironments (ITM). However, current senolytic strategies lack specificity for STCs and often cause off-target toxicity. Here, we first identified the antigen presenting potential of STCs in patient-derived tumor tissues and demonstrated their capacity for directly priming and inducing STC-specific CD8+ T cells. We thereafter engineered STC-derived nanovesicles for directly priming CD8+ T cells through their upregulated antigen-presenting machinery (termed as nano-APM). Upon systemic administration, nano-APMs specifically accumulated in the spleen and directly primed CD8⁺ T cell, thereby establishing STC-specific T cell pool. Based on these finding, we sequentially combining nano-APM with RT to achieve spatiotemporally-confined activation of anti-senescence immunity via RT-controlled tumor senescence induction. In preclinical mouse models of pancreatic ductal adenocarcinoma and bladder cancer, the sequential combination of the nano-APM with RT effectively eliminated STCs, reprogramed RT-induced ITM (e.g., 21.5-folds higher CD8+ T cell to Tregs ratio than the control group), and induced durable antitumor response. Overall, this study pioneered a STC-derived nanovesicle platform to directly prime splenic T cells and achieve spatiotemporally-confined senolysis for potentiating RT.

ORGANISM(S): Mus musculus

PROVIDER: GSE306978 | GEO | 2026/01/14

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 Senescent Tumor Cell-Derived Nanovesicle Directly Primes Splenic T cells to Potentiate Radiotherapy

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