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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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Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

Project description: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: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

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

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

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Tumor-derived biomimetic nanozyme with immune evasion ability for synergistically enhanced low dose radiotherapy.

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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PD-1 blockade reverses adaptive immune resistance induced by high-dose hypofractionated but not low-dose daily fractionated radiation.

Project description:Preclinical evidence suggests that high-dose hypofractionated ionizing radiation (IR) can enhance anti-tumor immunity and result in significant tumor control when combined with immune checkpoint blockade (ICB). However, low-dose daily fractioned IR used for many tumor types including head and neck squamous cell carcinoma results in lymphopenia and may be immunosuppressive. We compared immune correlates, primary tumor and abscopal tumor control rates following the addition of PD-1 mAb to either high-dose hypofractioned (8Gyx2) or low-dose daily fractionated (2Gyx10) IR in syngeneic models of cancer. When compared to 2Gyx10 IR, 8Gyx2 IR preserved peripheral and tumor-infiltrating CD8+ T-lymphocyte accumulation and activation and reduced peripheral and tumor gMDSC accumulation. Regulatory T-lymphocytes were largely unaltered. Type I and I IFN levels and expression of IFN-responsive MHC class I and PD-L1 was enhanced in tumors treated with 8Gyx2 compared to 2Gyx10 IR. Functionally, tumor-specific CD8+ T-lymphocyte IFN responses within tumor draining lymph nodes were enhanced following 8Gyx2 IR but suppressed following 2Gyx10 IR. When combined with PD-1 mAb, reversal of adaptive immune resistance and subsequent enhancement of CD8+ cell dependent primary and abscopal tumor control was observed following 8Gyx2 but not 2Gyx10 IR. These data strongly support that compared to daily fractionated low-dose IR, high-dose hypofractionated IR preserves or enhances anti-tumor immunity and, when combined with PD-1 mAb to reverse adaptive immune resistance, promotes anti-tumor immunity to control primary and distant tumors. These data critically inform the rational design of trials combining IR and ICB.

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Selective SIRP? blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance.

Project description:T cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-? (SIRP?), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRP?-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRP?, and not SIRP?/CD47, in humans remains unknown. We report a potent synergy between selective SIRP? blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRP? blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRP?/SIRP? blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRP? inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors.

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