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In situ tumor arrays reveal early environmental control of cancer immunity

ABSTRACT: In situ tumor arrays reveal early environmental control of cancer immunity

PROVIDER: PRJNA918643 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22952500.fastq.gz	Fastqsanger.gz
	SRR22952501.fastq.gz	Fastqsanger.gz
	SRR22952502.fastq.gz	Fastqsanger.gz
	SRR22952503.fastq.gz	Fastqsanger.gz
	SRR22952504.fastq.gz	Fastqsanger.gz

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Project description:The immune phenotype of a tumor is a key predictor of its response to immunotherapy. Patients who respond to immune checkpoint blockade generally present with tumors infiltrated by T cells, a phenotype referred to as ‘inflamed’. However, not all inflamed tumors respond to therapy, and even lower response rates occur among patients with tumors that lack T cells (‘desert’) or that spatially exclude T cells to the periphery of the tumor lesion (‘excluded’). Despite the importance of these tumor immune phenotypes in patients, little is known about their development, heterogeneity or dynamics due to the technical difficulty of modeling and tracking these features in situ. Here, we introduce STAMP (skin tumor array by microporation), a preclinical approach that combines in vivo high-throughput time-lapse imaging with next generation sequencing of tumor arrays. Using this approach, we follow the early formation of thousands of tumors to show that development of a given immune phenotype is not under strict control of tumor genetics or transcriptional state, but is also influenced by local features of the tumor microenvironment. Only the spatial organization of T cells, specifically early infiltration of T cells recruited by fibroblasts and monocytes into the core of a tumor, was predictive of functional T cell attack and tumor rejection. Evaluating the dynamic immune-history of tumors revealed that early conversion to the immune inflamed phenotype was predictive of therapy-induced or spontaneous tumor regression. Thus, STAMP captures the dynamic and complex relationships of spatial, cellular and molecular components of tumor progression and has the potential to translate therapeutic concepts into successful clinical strategies.

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Project description:The immune phenotype of a tumour is a key predictor of its response to immunotherapy1-4. Patients who respond to checkpoint blockade generally present with immune-inflamed5-7 tumours that are highly infiltrated by T cells. However, not all inflamed tumours respond to therapy, and even lower response rates occur among tumours that lack T cells (immune desert) or that spatially exclude T cells to the periphery of the tumour lesion (immune excluded)8. Despite the importance of these tumour immune phenotypes in patients, little is known about their development, heterogeneity or dynamics owing to the technical difficulty of tracking these features in situ. Here we introduce skin tumour array by microporation (STAMP)-a preclinical approach that combines high-throughput time-lapse imaging with next-generation sequencing of tumour arrays. Using STAMP, we followed the development of thousands of arrayed tumours in vivo to show that tumour immune phenotypes and outcomes vary between adjacent tumours and are controlled by local factors within the tumour microenvironment. Particularly, the recruitment of T cells by fibroblasts and monocytes into the tumour core was supportive of T cell cytotoxic activity and tumour rejection. Tumour immune phenotypes were dynamic over time and an early conversion to an immune-inflamed phenotype was predictive of spontaneous or therapy-induced tumour rejection. Thus, STAMP captures the dynamic relationships of the spatial, cellular and molecular components of tumour rejection and has the potential to translate therapeutic concepts into successful clinical strategies.

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In situ tumor arrays reveal early environmental control of cancer immunity

Project description:This SuperSeries is composed of the SubSeries listed below.

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