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

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

PROVIDER: PRJNA1109871 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28983915_1.fastq.gz	Fastqsanger.gz
	SRR28983915_2.fastq.gz	Fastqsanger.gz
	SRR28983916_1.fastq.gz	Fastqsanger.gz
	SRR28983916_2.fastq.gz	Fastqsanger.gz
	SRR28983917_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

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

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Project description:The combination of radiotherapy/chemoradiotherapy and immune checkpoint blockade can result in poor outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Here, we show that combining ATR inhibition (ATRi) with radiotherapy (RT) increases the frequency of activated NKG2A+PD-1+ T cells in animal models of HNSCC. Compared with the ATRi/RT treatment regimen alone, the addition of simultaneous NKG2A and PD-L1 blockade to ATRi/RT, in the adjuvant, post-radiotherapy setting induces a robust antitumour response driven by higher infiltration and activation of cytotoxic T cells in the tumour microenvironment. The efficacy of this combination relies on CD40/CD40L costimulation and infiltration of activated, proliferating memory CD8+ and CD4+ T cells with persistent or new T cell receptor (TCR) signalling, respectively. We also observe increased richness in the TCR repertoire and emergence of numerous and large TCR clonotypes that cluster based on antigen specificity in response to NKG2A/PD-L1/ATRi/RT. Collectively, our data point towards potential combination approaches for the treatment of HNSCC.

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