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Rationalistic Modulation of Immune Mechanisms Synergizes the Anti-Tumor Effects of Targeted Radiation Therapy in Pre-clinical Models

ABSTRACT: In this study, we employed a diverse set of pre-clinical syngeneic murine tumor models with varying immune profiles to investigate the immunological impact of radiotherapy. We observed that immunologically 'hot' tumors demonstrated stronger tumor growth inhibition (TGI) following RT compared to 'cold' tumors. Additionally, RT induced both pro- and anti-inflammatory shifts within the tumor immune microenvironment, with significant changes noted in the spleen and tumor-draining lymph nodes. Importantly, radiotherapy led to an intratumoral increase in proliferating CD8 T cells, while the population of proliferating macrophages was notably reduced. Our findings also reveal that STING deficiency compromises TGI, particularly in tumors with a high baseline population of macrophages expressing an interferon response signature. Moreover, we identified a synergistic tumor growth control effect when combining HPK1 deficiency with RT. Collectively, these results provide insights into the complex interplay between RT and the immune response, offering potential avenues for novel therapeutic combination strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE294347 | GEO | 2025/10/15

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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Rationalistic Modulation of Immune Mechanisms Synergizes the Anti-Tumor Effects of Targeted Radiation Therapy in Pre-clinical Models

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