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Sculpting the tumour microenvironment by combining radiotherapy and ATR inhibition for curative-intent adjuvant immunotherapy

ABSTRACT: Results of combining radiotherapy/chemoradiotherapy and immune checkpoint blockade have been disappointing in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). For such a potentially radiocurable disease, there remains an imperative to explore novel combination approaches. Here, we show that combining ATR inhibition with radiotherapy (ATRi/RT) increases the frequency of activated NKG2A/PD-1 double-positive T cells in animal models of HNSCC. Addition of dual anti-NKG2A/-PD-L1 blockade to ATRi/RT in the adjuvant, post-radiotherapy setting induces a robust antitumour response. Efficacy of the combination relies on CD40/CD40L costimulatory-mediated infiltration of activated/proliferative/memory CD8 and CD4 T cells with persistent or new T cell receptor (TCR) signalling, respectively. In this favourable therapeutic context, we reveal increased richness of the TCR repertoire and the emergence of numerous and large TCR clusters that share antigen specificity in response to combination therapy. Collectively, our data point towards promising combination approaches for future clinical testing in HNSCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE267158 | GEO | 2024/07/04

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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Sculpting the tumour microenvironment by combining radiotherapy and ATR inhibition for curative-intent adjuvant immunotherapy

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