Enhancing anti-tumour innate immunity by targeting the DNA damage response and pattern recognition receptors in combination with radiotherapy

Hak, Charleen M. L. Chan Wah; Rullan, Antonio; Patin, Emmanuel C.; Pedersen, Malin; Melcher, Alan; Harrington, Kevin J.

doi:10.3389/fonc.2022.971959

Cited by 19 publications

(12 citation statements)

References 313 publications

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“…Next, the expression of cell cycle checkpoint markers was studied to elucidate if 4T1 cells could effectively initiate DNA damage repair response ( Chan Wah Hak et al, 2022 ). The results showed that at a lower dose of Bi-212-MAA, there was increased activation of cell cycle checkpoint markers Chk1, Chk2, and Wee1; however, at higher dose levels, Chk1, Chk2, and Wee1 activation were comparable to control ( Figure 3C ).…”

Section: Resultsmentioning

confidence: 99%

Effective therapy with Bismuth-212 labeled macroaggregated albumin in orthotopic mouse breast tumor models

Kauffman

Singh

Morrison³

et al. 2023

Front. Chem.

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Intravascularly administered radiation therapy using beta (β-)-emitting radioisotopes has relied on either intravenously injected radiolabeled peptides that target cancer or radiolabeled microspheres that are trapped in the tumor following intra-arterial delivery. More recently, targeted intravenous radiopeptide therapies have explored the use of alpha (α)-particle emitting radioisotopes, but microspheres radiolabeled with α-particle emitters have not yet been studied. Here, FDA-approved macroaggregated albumin (MAA) particles were radiolabeled with Bismuth-212 (Bi-212-MAA) and evaluated using clonogenic and survival assays in vitro and using immune-competent mouse models of breast cancer. The in vivo biodistribution of Bi-212-MAA was investigated in Balb/c and C57BL/6 mice with 4T1 and EO771 orthotopic breast tumors, respectively. The same orthotopic breast cancer models were used to evaluate the treatment efficacy of Bi-212-MAA. Our results showed that macroaggregated albumin can be stably radiolabeled with Bi-212 and that Bi-212-MAA can deliver significant radiation therapy to reduce the growth and clonogenic potential of 4T1 and EO771 cells in vitro. Additionally, Bi-212-MAA treatment upregulated γH2AX and cleaved Caspase-3 expression in 4T1 cells. Biodistribution analyses showed 87–93% of the Bi-212-MAA remained in 4T1 and EO771 tumors 2 and 4 h after injection. Following single-tumor treatments with Bi-212-MAA there was a significant reduction in the growth of both 4T1 and EO771 breast tumors over the 18-day monitoring period. Overall, these findings showed that Bi-212-MAA was stably radiolabeled and inhibited breast cancer growth. Bi-212-MAA is an exciting platform to study α-particle therapy and will be easily translatable to larger animal models and human clinical trials.

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Section: Resultsmentioning

confidence: 99%

Effective therapy with Bismuth-212 labeled macroaggregated albumin in orthotopic mouse breast tumor models

Kauffman

Singh

Morrison³

et al. 2023

Front. Chem.

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“…Moreover, analogous to the combination studies with radiotherapy, long-lasting antitumor immunity was also observed in a murine colorectal model when ATR inhibition was combined with anti-PD-L1 antibodies and platinum-based chemotherapy ( 52 ). Promising preclinical results have led to several ongoing early-phase clinical trials with immune checkpoint blockade in combination with ATR inhibitors, and at least one of these studies addresses the triple-treatment with radiotherapy [reviewed in ( 11 , 53 )]. Of note is that even the co-treatment of radiotherapy and immune checkpoint blockade is far from fully developed.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, recent preclinical studies suggest that ATR inhibition can increase the immunostimulatory effects of radiotherapy. This has been demonstrated in multiple murine models in vivo , where ATR inhibition combined with irradiation caused activation of CD8 + T cells, dendritic cells and natural killer cells, induction of immunological memory and less regulatory T cell-mediated immunosuppression ( 11 , 19 – 21 ). Nevertheless, the underlying molecular mechanisms are incompletely understood.…”

Section: Introductionmentioning

confidence: 90%

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Immunogenic cell death after combined treatment with radiation and ATR inhibitors is dually regulated by apoptotic caspases

Eek Mariampillai,

Hauge,

Kongsrud

et al. 2023

Front. Immunol.

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IntroductionInhibitors of the ATR kinase act as radiosensitizers through abrogating the G2 checkpoint and reducing DNA repair. Recent studies suggest that ATR inhibitors can also increase radiation-induced antitumor immunity, but the underlying immunomodulating mechanisms remain poorly understood. Moreover, it is poorly known how such immune effects relate to different death pathways such as caspase-dependent apoptosis. Here we address whether ATR inhibition in combination with irradiation may increase the presentation of hallmark factors of immunogenic cell death (ICD), and to what extent caspase activation regulates this response.MethodsHuman lung cancer and osteosarcoma cell lines (SW900, H1975, H460, U2OS) were treated with X-rays and ATR inhibitors (VE822; AZD6738) in the absence and presence of a pan-caspase inhibitor. The ICD hallmarks HMGB1 release, ATP secretion and calreticulin surface-presentation were assessed by immunoblotting of growth medium, the CellTiter-Glo assay and an optimized live-cell flow cytometry assay, respectively. To obtain accurate measurement of small differences in the calreticulin signal by flow cytometry, we included normalization to a barcoded control sample.ResultsExtracellular release of HMGB1 was increased in all the cell lines at 72 hours after the combined treatment with radiation and ATR inhibitors, relative to mock treatment or cells treated with radiation alone. The HMGB1 release correlated largely – but not strictly – with loss of plasma membrane integrity, and was suppressed by addition of the caspase inhibitor. However, one cell line showed HMGB1 release despite caspase inhibition, and in this cell line caspase inhibition induced pMLKL, a marker for necroptosis. ATP secretion occurred already at 48 hours after the co-treatment and did clearly not correlate with loss of plasma membrane integrity. Addition of pan-caspase inhibition further increased the ATP secretion. Surface-presentation of calreticulin was increased at 24-72 hours after irradiation, but not further increased by either ATR or caspase inhibition.ConclusionThese results show that ATR inhibition can increase the presentation of two out of three ICD hallmark factors from irradiated human cancer cells. Moreover, caspase activation distinctly affects each of the hallmark factors, and therefore likely plays a dual role in tumor immunogenicity by promoting both immunostimulatory and -suppressive effects.

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“…Combining therapy with existing therapies such as immune checkpoint inhibitors still poses numerous challenges. 134 There is a need to maximize the immunestimulatory effects of radioimmunotherapy. 135 CBTH is a strong candidate for wider dissemination and implementation in the cancer population.…”

Section: Radiation and Immunotherapymentioning

confidence: 99%

Radiation induced therapeutic effects in cancerous and tumor cells: A review

Upadhyay¹,

Rai²

2023

JSRT

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Present review article describes use of radiation and radionuclides on cancer and cancer cell therapeutics. It also sketches out cumulative effects of radiation exposure received by the patients during cancer diagnostics. Though, in cancer therapeutics a selected and permissible dose is provided in several cycles to ablate the neoplastic cells and improve the condition of patient, but radiation harms surrounding cells and imparts negative effects on biology of cells. Ionizing radiation (IR) promotes cancer cell death through cytotoxicity. This article emphasizes both remedial effects and biological effects of radiation and radio-resistance in cells. It suggests safe use of radionucleides by encapsulating them in nanomaterials so as to use it alternate to chemotherapy to destroy various cancer types to enhance the survival of normal cells. This article explains effect of ionizing and non-ionizing radiation on cellular metabolism and genetics.

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Enhancing anti-tumour innate immunity by targeting the DNA damage response and pattern recognition receptors in combination with radiotherapy

Cited by 19 publications

References 313 publications

Effective therapy with Bismuth-212 labeled macroaggregated albumin in orthotopic mouse breast tumor models

Effective therapy with Bismuth-212 labeled macroaggregated albumin in orthotopic mouse breast tumor models

Immunogenic cell death after combined treatment with radiation and ATR inhibitors is dually regulated by apoptotic caspases

Radiation induced therapeutic effects in cancerous and tumor cells: A review

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