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ScRNA-seq reveals tumor microenvironment remodeling induced by local intervention-based immunotherapy

ABSTRACT: scRNA-seq reveals tumor microenvironment remodeling induced by local intervention-based immunotherapy

PROVIDER: PRJNA633139 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11798500_1.fastq.gz	Fastqsanger.gz
	SRR11798500_2.fastq.gz	Fastqsanger.gz
	SRR11798501_1.fastq.gz	Fastqsanger.gz
	SRR11798501_2.fastq.gz	Fastqsanger.gz
	SRR11798502_1.fastq.gz	Fastqsanger.gz

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scRNA-seq reveals tumor microenvironment remodeling induced by local intervention-based immunotherapy

Project description:Laser immunotherapy (LIT) combines local photothermal therapy (PTT), to disrupt tumor homeostasis and release tumor antigens, and an intratumorally administered immunostimulant, N-dihydrogalactochitosan (GC), to induce antitumor immune responses. We performed single-cell RNA sequencing on tumor-infiltrating leukocytes of MMTV-PyMT mouse mammary tumors to determine LIT-induced myeloid and lymphoid compartment remodeling. Analysis of 49,380 single cell transcriptomes from different treatment groups revealed proinflammatory IFNa, IFNg, and TNFa cytokine signaling pathways were enriched in both lymphoid and myeloid cells isolated from LIT-treated tumors. Interestingly, the CD4+ and CD8+ T cells in LIT and GC treated tumors resided in an activated state while immune cells in untreated and PTT-treated tumors remained in a neutral/resting state. Additionally, monocytes recruited into the LIT-treated tumors were driven towards proinflammatory M1-like macrophage phenotypes or monocyte-derived dendritic cells. Our results reveal that LIT prompts immunological remodeling of the tumor microenvironment by initiating broad proinflammatory responses to drive antitumor immunity.

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Project description:Radiotherapy (RT) primes the immune system against cancer antigens but fails to trigger effective antitumor responses due to concomitant induction of immunosuppressive factors. To expand the benefits of RT, we combine local radiation with immuno-gene therapy by harnessing the ability of ionizing radiation to enhance AAV-mediated tumor transduction. To successfully deliver AAV-based local immunotherapy and restrict transgene expression within tumors, we designed a recombinant AAV that expresses IL-12 through an interferon (IFN)-inducible promoter (AAV-iIL12). Local administration of AAV-iIL12 upon RT results in marked and durable elevation of intratumor IL-12 with minor and transient systemic release. This strategy generates a highly immunostimulatory tumor microenvironment (TME) leading to strong antitumor responses in an IFNg-dependent manner. Moreover, local treatment with RT and AAV-iIL12 elicits systemic antitumor immunity with marked CD8+ T cell infiltration and regression of distant tumors. Our work shows that radiation coupled with AAV-based immuno-gene delivery is a novel, efficient and safe approach that can be exploited as cancer therapy.

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