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Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

ABSTRACT: Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

PROVIDER: PRJNA695240 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13559384.fastq.gz	Fastqsanger.gz
	SRR13559385.fastq.gz	Fastqsanger.gz
	SRR13559386.fastq.gz	Fastqsanger.gz
	SRR13559387.fastq.gz	Fastqsanger.gz
	SRR13559388.fastq.gz	Fastqsanger.gz

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Integrated Profiling Reveals Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

Project description:Integrated Profiling Reveals Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

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Metronomic Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

Project description:Metronomic Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

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Metronomic Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

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Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

Project description:The development of approaches for inflaming cold tumors is critical for increasing response to immunotherapy. Here we report that low-dose radiotherapy (LDRT) in mice promotes tumor T-cell inflammation and enables responsiveness to combinatorial immunotherapyin an interferon-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity, and depended on both cytotoxic CD4+and CD8+T cells. LDRTinduced predominantly CD4+cells which exhibited features of exhausted effector and cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, and a novel subset of dendritic cells with activated phenotype that expressed the NKG2D ligand Rae1. Finally, tumor immune rejection was critically dependent on the NKG2D pathway. We translated these findings toa phase I clinical trial. Like in mice, combinatorial treatmenttriggered peripheral T-cell mobilization and resulted in important tumor T-cell infiltration, predominantly of CD4+cells and with Th1 signatures, observed only in patients with immune desert tumors who responded to a novel combination of LDRT, low dose cyclophosphamide and immune checkpoint blockade therapy.These results suggest the novel possibility of rationally combining LDRT with immune checkpoint therapy for the treatment of cold tumors, based on the simultaneous activation of antitumoral innate and adaptive immunity

2021-08-13 | GSE165612 | GEO

Metronomic Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

Project description:We report major tumor regressions in a subset of advanced cancer patients for which cold tumors were treated with low-dose radiotherapy, cyclophosphamide, aspirin, and ICB (NCT03728179). Unbiased analyses of biopsies revealed T-cell infiltration, up-regulation of type I IFN, and Th1 signatures as well as down-regulation of M2 macrophage and epithelial to mesenchymal transition gene-signatures, and a more oligoclonal TCR repertoire after radio-combinatorial immunotherapy, in responding patients.

2021-08-16 | GSE167455 | GEO

Metronomic Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

Project description:The development of approaches for inflaming cold tumors is critical for increasing response to immunotherapy (IMT) reliant upon the re-invigoration of T cells for tumor control. Here we report, in a pre-clinical advanced ID8 ovarian cancer model, that metronomic low-dose radiotherapy (LDRT; 1 Gy) promotes T-cell infiltration and enables responsiveness to treatment including low-dose cyclophosphamide (CP), and combinatorial IMT comprising immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4, and anti-CD40 agonist antibody, for significant tumor control and survival. Responses to this radio-combinatorial immunotherapy (RACIM) relied upon re-programming of both innate and adaptive immunity. We further identified RACIM-induced intratumoral dendritic cell states with co-stimulatory capacity and expressing the stress ligand RAE1, as well as of polyfunctional NKG2D+TCF1-PD1+CD4+T cells. We further report major tumor regressions in a subset of advanced cancer patients for which cold tumors were treated with LDRT, CP, aspirin, and ICB (NCT03728179). Unbiased analyses of biopsies revealed T-cell infiltration, up-regulation of type I IFN, and Th1 signatures as well as down-regulation of M2 macrophage and epithelial to mesenchymal transition gene-signatures, and a more oligoclonal TCR repertoire after RACIM, in responding patients.

2021-08-16 | GSE166303 | GEO

Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy.

Project description:Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell-infiltrated tumors. SIGNIFICANCE: Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4+ effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors.This article is highlighted in the In This Issue feature, p. 1.

| S-EPMC9401506 | biostudies-literature

Integrated Profiling Reveals Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

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

2021-08-13 | GSE169742 | GEO

Immunotherapy study of phagocytosis checkpoint blockade in combination with radiotherapy

Project description:Immunotherapy study of phagocytosis checkpoint blockade in combination with radiotherapy

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Radiotherapy and IFNγ treatment effect on transcriptome in HT1080 cells

Project description:Immune checkpoint blockade is a powerful oncologic treatment modality for a wide variety of human malignancies. Randomized clinical trials are assessing how best to interdigitate this treatment modality with traditional therapies including radiotherapy. A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities including radiotherapy. Here, we demonstrate that radiotherapy induces tumor cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor cell ferroptosis. Mechanistically, IFN derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently, yet synergistically repress SLC7A11, a unit of the glutamate-cystine antiporter xc-, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy.

2020-09-23 | GSE137946 | GEO

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