Radiation dose-fractionation effects on immune modulation in murine mammary tumors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE162418 | GEO | 2020/12/01
REPOSITORIES: GEO
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Project description:Radiation dose-fractionation effects on immune modulation in murine mammary tumors
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Project description:The immunologic effects of radiation (RT) are influenced by dose and each may be optimized over a unique dose range. We hypothesized that delivering a heterogenous dose of RT would enhance anti-tumor immunity compared to homogenous RT in combination with immune checkpoint blockade (ICI). Using a point source, we delivered a spectrum of dose (~2-32 Gy) to the primary tumor and observed superior systemic immunity in models of metastatic cancer compared to low (2 Gy), moderate (8 Gy), or high (20 Gy) dose homogenous RT. Heterogeneity in RT dose resulted in spatial heterogeneity in gene expression and immune cell infiltration. Moreover, heterogenous RT optimally engaged multiple immune signaling pathways with diverse dose response relationships whereas responses to homogenous RT treatment groups were limited. Single cell RNAseq demonstrated unique enrichment of immune cell populations between each homogenous RT dose group, with several of these dose-dependent changes also represented in the heterogeneously treated tumors, with engagement of both lymphoid and myeloid compartments. This optimized activation of multiple immune mechanisms with distinct dose-dependent profiles within a single tumor may underlie a greater capacity of RT heterogeneity to augment anti-tumor immune response when combined with ICI, as compared to homogenous dose RT.
2024-07-12 | GSE234159 | GEO
Project description:The immunologic effects of radiation (RT) are influenced by dose and each may be optimized over a unique dose range. We hypothesized that delivering a heterogenous dose of RT would enhance anti-tumor immunity compared to homogenous RT in combination with immune checkpoint blockade (ICI). Using a point source, we delivered a spectrum of dose (~2-32 Gy) to the primary tumor and observed superior systemic immunity in models of metastatic cancer compared to low (2 Gy), moderate (8 Gy), or high (20 Gy) dose homogenous RT. Heterogeneity in RT dose resulted in spatial heterogeneity in gene expression and immune cell infiltration. Moreover, heterogenous RT optimally engaged multiple immune signaling pathways with diverse dose response relationships whereas responses to homogenous RT treatment groups were limited. Single cell RNAseq demonstrated unique enrichment of immune cell populations between each homogenous RT dose group, with several of these dose-dependent changes also represented in the heterogeneously treated tumors, with engagement of both lymphoid and myeloid compartments. This optimized activation of multiple immune mechanisms with distinct dose-dependent profiles within a single tumor may underlie a greater capacity of RT heterogeneity to augment anti-tumor immune response when combined with ICI, as compared to homogenous dose RT.
2024-07-12 | GSE234157 | GEO
Project description:Background: Effective radiation treatment (RT) for recurrent nasopharyngeal cancers (NPC), featuring an intrinsic hypoxic sub-volume, remains a clinical challenge. Lack of disease‐specific in-vitro models, together with difficulties in establishing patient derived xenograft (PDX) models, have further hindered development of personalized therapeutic options. Methods: Here in, we established two NPC organoid lines from recurrent NPC PDX models and further characterized and compared these models with original patient tumors using RNA sequencing analysis. Organoids were cultured in hypoxic conditions to examine the effects of hypoxia and radioresistance. These models were then utilized to determine the radiobiological parameters, such as α/β ratio and oxygen enhancement ratio (OER), characteristic to radiosensitive normoxic and radioresistant hypoxic NPC, using simple dose-survival data analytic tools. The results were further validated in-vitro and in-vivo, to determine the optimal boost dose and fractionation regimen required to achieve effective NPC tumor regression. Results: Despite the differences in tumor microenvironment due to the lack of human stroma, RNA sequencing analysis revealed good correlation of NPC PDX and organoid models with patient tumors. Additionally, the established models also mimicked inter-tumoral heterogeneity. Hypoxic NPC organoids were highly radioresistant and had high α/β ratio compared to its normoxic counterparts. In-vitro and in-vivo fractionation studies showed that hypoxic NPC was less sensitive to RT fractionation scheme and required a large bolus dose or 1.4 times of the fractionated dose that was effective against normoxic cells in order to compensate for oxygen deficiency. Conclusion: This study is the first direct experimental evidence to predict optimal RT boost dose required to cause sufficient damage to recurrent hypoxic NPC tumor cells, which can be further used to develop dose-painting algorithms in clinical practice.
2021-01-12 | GSE164544 | GEO
Project description:While modern radiotherapy technologies can precisely deliver higher doses of radiation to tumors; thus, reducing overall radiation exposure to normal tissues, moderate dose and normal tissue toxicity still remains a significant limitation. The present study profiled the global effects on transcript and miR expression in Human Coronary Artery Endothelial Cells (HCAECs) using single-dose irradiation (SD, 10Gy) or multi-fractionated irradiation (MF, 2Gy x 5) regimens. Longitudinal timepoints were collected after a SD or final dose of MF irradiation for analysis using Agilent Human Gene Expression and miRNA microarray platforms. Compared to SD, the exposure to MF resulted in robust transcript and miR expression changes in terms of the number and magnitude. For data analysis, statistically significant mRNAs (2-fold) and miRs (1.5-fold) were processed by Ingenuity Pathway Analysis (IPA) to uncover miRs associated with target transcripts from several cellular pathways post-irradiation. Interestingly, MF radiation induced a cohort of mRNAs and miRs that coordinate the induction of immune response pathway under tight regulation. Additionally, mRNAs and miRs associated with DNA replication, recombination and repair, apoptosis, cardiovascular events and angiogenesis were revealed. Human Coronary Artery Endothelial Cells (HCAECs) were irradiated in a PANTAK high frequency X-ray generator (Precision X-ray Inc., N. Bedford, CT), operated at 300kV and 10MA. The dose rate was 1.6 Gy per min. Cells were plated into T75cm2 flasks (1-1.5 x 10^6 for single dose radiation and 0.6-0.8 x 10^6 for fractionated radiation). After 24h, cells were exposed to a total of 10 Gy radiation administered either as a single-dose radiation (SD), or as multi-fractionated radiation of 2 Gy x 5 (MF). These non-isoeffective doses were selected to simulate clinical hypofractionated and conventionally fractionated radiotherapy regimens. For the MF protocol, cells were exposed to 2 Gy radiation twice a day, at 6h interval. The cells were approximately 90% confluent at the time of harvesting. For both protocols, radiation-induced changes were analyzed at 6h and 24h after a SD and 6h and 24h after the final dose of fractionated irradiation. Separate controls were maintained for SD and MF radiation protocols.
2014-07-01 | E-GEOD-56824 | biostudies-arrayexpress
Project description:While modern radiotherapy technologies can precisely deliver higher doses of radiation to tumors; thus, reducing overall radiation exposure to normal tissues, moderate dose and normal tissue toxicity still remains a significant limitation. The present study profiled the global effects on transcript and miR expression in Human Coronary Artery Endothelial Cells (HCAECs) using single-dose irradiation (SD, 10Gy) or multi-fractionated irradiation (MF, 2Gy x 5) regimens. Longitudinal timepoints were collected after a SD or final dose of MF irradiation for analysis using Agilent Human Gene Expression and miRNA microarray platforms. Compared to SD, the exposure to MF resulted in robust transcript and miR expression changes in terms of the number and magnitude. For data analysis, statistically significant mRNAs (2-fold) and miRs (1.5-fold) were processed by Ingenuity Pathway Analysis (IPA) to uncover miRs associated with target transcripts from several cellular pathways post-irradiation. Interestingly, MF radiation induced a cohort of mRNAs and miRs that coordinate the induction of immune response pathway under tight regulation. Additionally, mRNAs and miRs associated with DNA replication, recombination and repair, apoptosis, cardiovascular events and angiogenesis were revealed. Human Coronary Artery Endothelial Cells (HCAECs) were irradiated in a PANTAK high frequency X-ray generator (Precision X-ray Inc., N. Bedford, CT), operated at 300kV and 10MA. The dose rate was 1.6 Gy per min. Cells were plated into T75cm2 flasks (1-1.5 x 10^6 for single dose radiation and 0.6-0.8 x 10^6 for fractionated radiation). After 24h, cells were exposed to a total of 10 Gy radiation administered either as a single-dose radiation (SD), or as multi-fractionated radiation of 2 Gy x 5 (MF). These non-isoeffective doses were selected to simulate clinical hypofractionated and conventionally fractionated radiotherapy regimens. For the MF protocol, cells were exposed to 2 Gy radiation twice a day, at 6h interval. The cells were approximately 90% confluent at the time of harvesting. For both protocols, radiation-induced changes were analyzed at 6h and 24h after a SD and 6h and 24h after the final dose of fractionated irradiation. Separate controls were maintained for SD and MF radiation protocols.
2014-07-01 | E-GEOD-57059 | biostudies-arrayexpress
Project description:Radiotherapy is under investigation in the clinic for its ability to induce an in situ vaccine and enhance responses to immune checkpoint inhibitors and other immunotherapies. A variety of radiation doses and delivery schedules have been used to induce anti-tumor T cells in preclinical studies. However, the mechanisms bu which radiation induces anti-tumor T cells against poorly immunogenic tumors remain incompletely understood. In this study, we investigated changes in gene expression in mouse mammary carcinoma TSA tumors after a single dose (SD) of 20 Gy and a multi-fraction (MF) radiation regimen of 3x8Gy. To this end, TSA cells were injected into syngeneic BALB/c mice. When tumors became palpable, they were treated with local radiation therapy (RT) and harvested 4 or 24 hours later for gene expression analysis. The genome-wide microarray analysis showed key differences between SD and MF RT that may explain the differential ability of these two RT regimens to synergize with immune checkpoint inhibitors (Dewan et al., Clin Cancer Res 2009).
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Project description:Lignocellulose fractionation by microbial consortia
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Project description:While modern radiotherapy technologies can precisely deliver higher doses of radiation to tumors; thus, reducing overall radiation exposure to normal tissues, moderate dose and normal tissue toxicity still remains a significant limitation. The present study profiled the global effects on transcript and miR expression in Human Coronary Artery Endothelial Cells (HCAECs) using single-dose irradiation (SD, 10Gy) or multi-fractionated irradiation (MF, 2Gy x 5) regimens. Longitudinal timepoints were collected after a SD or final dose of MF irradiation for analysis using Agilent Human Gene Expression and miRNA microarray platforms. Compared to SD, the exposure to MF resulted in robust transcript and miR expression changes in terms of the number and magnitude. For data analysis, statistically significant mRNAs (2-fold) and miRs (1.5-fold) were processed by Ingenuity Pathway Analysis (IPA) to uncover miRs associated with target transcripts from several cellular pathways post-irradiation. Interestingly, MF radiation induced a cohort of mRNAs and miRs that coordinate the induction of immune response pathway under tight regulation. Additionally, mRNAs and miRs associated with DNA replication, recombination and repair, apoptosis, cardiovascular events and angiogenesis were revealed.
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