Abstract 2063
Background
ATR inhibitors (ATRi) are in early phase clinical trials and have been shown to sensitise to chemotherapy and radiotherapy (RT) in preclinical data. No data have been published about the effect of these drugs on the tumour microenvironment. We demonstrate significant modulation of the immune microenvironment by ATRi + RT.
Methods
We used an immunocompetent mouse model of HPV-driven malignancies (TC1) to investigate the effect of the ATRi, AZD6738, in combination with RT 8 Gy in 4 fractions. Gene expression analysis, flow cytometry and cytokine quantification were used.
Results
There was sensitisation to RT by ATRi in this model. ATRi + RT caused a marked increase in a number of adaptive immune cells infiltrating the tumour at 5 days after treatment. There were significantly more dendritic cells, macrophages, and myeloid-derived suppressor cells after ATRi + RT. We also identified increased numbers of CD3+ and NK cells after the combination treatment. Transcriptional analysis found evidence of increased T-cell activation with the combination therapy. We found evidence of an interferon (IFN) response, with transcriptional upregulation of IFN-stimulated genes including those playing a role in nucleic acid sensing: Ddx58/RIG-I, and Ifih1/MDA5, Zbp1/DAI and Ddx60. We identified significant modulation of cytokine gene expression (CCL2, CCL5, CXCL10), and found that cultured tumour cells secreted CCL3, CCL5 and CXCL10 after ATRi + RT. We hypothesise that DNA damage and micronucleus formation caused by ATR + RT (as previously reported by us, Dillon et al. MCT 2016;16:25-34) leads to an IFN response through activation of nucleic acid sensing pathways, leading to influx of innate immune cells.
Conclusions
To our knowledge this is the first comprehensive analysis of the immune tumour microenvironment after radiation with a radiosensitising targeted drug. Further understanding of the effect of this combination on immune response may allow modulation to maximise tumour control through activation of anti-tumour immunity. MTD is a CRUK clinical research fellow. AZD6738 provided by AstraZeneca. MM, KJH joint senior authors.
Clinical trial identification
Legal entity responsible for the study
The Institute of Cancer Research.
Funding
Cancer Research UK.
Editorial Acknowledgement
Disclosure
M.T. Dillon: Co-investigator on clinical study of AZD6738 which is partially funded by AstraZeneca. A. Melcher: Compensated consultant/advisor and received honoraria: Amgen, BMS, Merck Serono; Research funding: Oncolytics Biotech Inc. K.J. Harrington: Payment for consulting fees: Amgen, AstraZeneca/Medimmune, BMS, Lytix Biopharma, MSD, Merck, Oncos Therapeutics, Pfizer, Viralytics Inc.; Research grant funding: MSD, Oncolytics Biotech., Viralytics Inc. All other authors have declared no conflicts of interest.
Resources from the same session
3816 - A prediction panel with DNA methylation biomarkers for lung adenocarcinoma
Presenter: Nan Shen
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
5242 - Novel genomic classifier for early stage colorectal cancer patients
Presenter: Elisabeth Letellier
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
5404 - Baseline Blood Immune Profiling to Predict Response to antiPD-1 in Patients with Advanced Non-Small Cell Lung Cancer
Presenter: Emanuela Romano
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
5462 - Evaluation of clinicopathological and molecular criterias for screening of exonucleasic domain POLE (edPOLE) mutated patients in proficient Mismatch Repair (pMMR) colorectal and endometrial cancers.
Presenter: Justine Cohen
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
5465 - Immune prognostic index (IPI) and Hyper-Progressive disease (HPD) in patients (pts) exposed to targeted agents (TAs) in Phase 1 trials (Ph1T): can lessons from immune checkpoint inhibitors (ICIs) be translated to other scenarios?
Presenter: Ignacio Matos Garcia
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
5742 - Combination of baseline LDH, performance status and age to identify solid tumor patients with higher probability of response to anti-PD1 and PDL1 monoclonal antibodies
Presenter: Maria Silvia Cona
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
5790 - Effects of concomitant genetic alterations on cancer patient overall survival
Presenter: Yu Wang
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
5144 - Circulating Exosomal Integrin _v_5 Predicts Liver Metastasis and Prognosis in Human Colorectal Cancer
Presenter: Dake Chu
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
5149 - Circulating and tumor-associated caspase-4: a novel diagnostic and prognostic biomarker for Non-Small Cell Lung Cancer patients?
Presenter: Rosalinda Sorrentino
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
5673 - Smokers and COPD patients have high circulating caspase-4 levels: is it an alarm?
Presenter: Michela Terlizzi
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract