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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE169742 | GEO | 2021/08/13

REPOSITORIES: GEO

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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

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: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.

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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.

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Project description:High doses of radiation can cause serious side effects and efficient radiosensitizers are urgently needed. To overcome this problem, we developed a biomimetic nanozyme system (CF) by coating pyrite (FeS2) into tumor-derived exosomes for enhanced low-dose radiotherapy (RT). CF system give FeS2 with immune escape and homologous targeting abilities. After administration, CF with both glutathione oxidase (GSH-OXD) and peroxidase (POD) activities can significantly lower the content of GSH in tumor tissues and catalyze intracellular hydrogen peroxide (H2O2) to produce a large amount of ·OH for intracellular redox homeostasis disruption and mitochondria destruction, thus reducing RT resistance. Experiments in vivo and in vitro showed that combining CF with RT (2 Gy) can provide a substantial suppression of tumor proliferation. This is the first attempt to use exosomes bionic FeS2 nanozyme for realizing low-dose RT, which broaden the prospects of nanozymes.

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