ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation
Open accessAbstract
DNA-damaging chemotherapy and radiation therapy are integrated into the treatment paradigm of the majority of cancer patients. Recently, immunotherapy that targets the immunosuppressive interaction between programmed death 1 (PD-1) and its ligand PD-L1 has been approved for malignancies including non-small cell lung cancer, melanoma, and head and neck squamous cell carcinoma. ATR is a DNA damage-signaling kinase activated at damaged replication forks, and ATR kinase inhibitors potentiate the cytotoxicity of DNA-damaging chemotherapies. We show here that the ATR kinase inhibitor AZD6738 combines with conformal radiation therapy to attenuate radiation-induced CD8+ T cell exhaustion and potentiate CD8+ T cell activity in mouse models of Kras-mutant cancer. Mechanistically, AZD6738 blocks radiation-induced PD-L1 upregulation on tumor cells and dramatically decreases the number of tumor-infiltrating Tregs. Remarkably, AZD6738 combines with conformal radiation therapy to generate immunologic memory in complete responder mice. Our work raises the possibility that a single pharmacologic agent may enhance the cytotoxic effects of radiation while concurrently potentiating radiation-induced antitumor immune responses.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ATR inhibitors counteract the ability of radiation therapy to increase PD-L1.
“Moreover, ATR inhibitors appear to offset the ability of RT to drive PD-L1 upregulation (Vendetti et al., 2018) and hence synergize with RT and ICIs in the control of mouse hepatocellular carcinomas established in immunocompetent hosts (Sheng et al., 2020).”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Vendetti et al., 2018
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The blockade of immune checkpoints in cancer immunotherapy
Pardoll, D. M. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3239 · Cited by 13,838 · see citing works
Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628 · see citing works
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer
Brahmer, J. R., Tykodi, S. S., Chow, L. Q. M., Hwu, W.-J., Topalian, S. L., Hwu, P., Drake, C. G., Camacho, L. H., Kauh, J., Odunsi, K., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200694 · Cited by 7,945 · see citing works
PD-1 and Its Ligands in Tolerance and Immunity
Keir, M. E., Butte, M. J., Freeman, G. J., & Sharpe, A. H. (2008) · Annual Review of Immunology · doi:10.1146/annurev.immunol.26.021607.090331 · Cited by 5,378 · see citing works
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck
Ferris, R. L., Blumenschein, G., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., Harrington, K., Kasper, S., Vokes, E. E., Even, C., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1602252 · Cited by 5,101 · see citing works
Self-citationTumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion
Dong, H., Strome, S. E., Salomao, D. R., Tamura, H., Hirano, F., Flies, D. B., Roche, P. C., Lu, J., Zhu, G., Tamada, K., et al. (2002) · Nature Medicine · doi:10.1038/nm730 · Cited by 5,025 · see citing works
Molecular and cellular insights into T cell exhaustion
Wherry, E. J., & Kurachi, M. (2015) · Nature Reviews Immunology · doi:10.1038/nri3862 · Cited by 4,652 · see citing works
The DNA Damage Response: Making It Safe to Play with Knives
Ciccia, A., & Elledge, S. J. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.019 · Cited by 4,368 · see citing works
Restoring function in exhausted CD8 T cells during chronic viral infection
Barber, D. L., Wherry, E. J., Masopust, D., Zhu, B., Allison, J. P., Sharpe, A. H., Freeman, G. J., & Ahmed, R. (2005) · Nature · doi:10.1038/nature04444 · Cited by 3,960 · see citing works
Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer
Twyman-Saint Victor, C., Rech, A. J., Maity, A., Rengan, R., Pauken, K. E., Stelekati, E., Benci, J. L., Xu, B., Dada, H., Odorizzi, P. M., et al. (2015) · Nature · doi:10.1038/nature14292 · Cited by 2,434 · see citing works
Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice
Deng, L., Liang, H. L., Burnette, B., Beckett, M., Darga, T. E., Weichselbaum, R. R., & Fu, Y. (2014) · Journal of Clinical Investigation · doi:10.1172/jci67313 · Cited by 2,101 · see citing works
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R., Kuchroo, V. K., & Anderson, A. C. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100643 · Cited by 2,072 · see citing works
Blackburn, S. D., Shin, H., Haining, W. N., Zou, T., Workman, C. J., Polley, A., Betts, M. R., Freeman, G. J., Vignali, D. A. A., & Wherry, E. J. (2009) · Nature Immunology · doi:10.1038/ni.1679 · Cited by 2,062 · see citing works
Reits, E. A., Hodge, J. W., Herberts, C. A., Groothuis, T. A., Chakraborty, M., K.Wansley, E., Camphausen, K., Luiten, R. M., de Ru, A. H., Neijssen, J., et al. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20052494 · Cited by 1,737 · see citing works
Spranger, S., Spaapen, R. M., Zha, Y., Williams, J., Meng, Y., Ha, T. T., & Gajewski, T. F. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3006504 · Cited by 1,677 · see citing works
Lee, Y., Auh, S. L., Wang, Y., Burnette, B., Wang, Y., Meng, Y., Beckett, M., Sharma, R., Chin, R., Tu, T., et al. (2009) · Blood · doi:10.1182/blood-2009-02-206870 · Cited by 1,324 · see citing works
Acquired Resistance to Fractionated Radiotherapy Can Be Overcome by Concurrent PD-L1 Blockade
Dovedi, S. J., Adlard, A. L., Lipowska‐Bhalla, G., McKenna, C., Jones, S., Cheadle, E. J., Stratford, I. J., Poon, E., Morrow, M., Stewart, R. A., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1258 · Cited by 1,316 · see citing works
Fourcade, J., Sun, Z., Benallaoua, M., Guillaume, P., Luescher, I. F., Sander, C., Kirkwood, J. M., Kuchroo, V., & Zarour, H. M. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100637 · Cited by 1,307 · see citing works
<i>ATR</i> disruption leads to chromosomal fragmentation and early embryonic lethality
Brown, E. J., & Baltimore, D. (2000) · Genes & Development · doi:10.1101/gad.14.4.397 · Cited by 951 · see citing works
Zeng, J., See, A. P., Phallen, J., Jackson, C. M., Belcaid, Z., Ruzevick, J., Durham, N., Meyer, C., Harris, T. J., Albesiano, E., et al. (2013) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2012.12.025 · Cited by 889 · see citing works
Self-citationBurnette, B., Liang, H. L., Lee, Y., Chlewicki, L. K., Khodarev, N. N., Weichselbaum, R. R., Fu, Y., & Auh, S. L. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-2820 · Cited by 883 · see citing works
Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway
Ohaegbulam, K. C., Assal, A., Lázár‐Molnár, E., Yao, Y., & Zang, X. (2014) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2014.10.009 · Cited by 846 · see citing works
DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells
Sato, H., Niimi, A., Yasuhara, T., Permata, T. B. M., Hagiwara, Y., Isono, M., Nuryadi, E., Sekine, R., Oike, T., Kakoti, S., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01883-9 · Cited by 710 · see citing works
Regulation of PD‐1, PD‐L1, and PD‐L2 expression during normal and autoimmune responses
Liang, S. C., Latchman, Y. E., Buhlmann, J. E., Tomczak, M. F., Horwitz, B. H., Freeman, G. J., & Sharpe, A. H. (2003) · European Journal of Immunology · doi:10.1002/eji.200324228 · Cited by 635 · see citing works
Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR
Reaper, P. M., Griffiths, M. R., Long, J. M., Charrier, J.-D., MacCormick, S., Charlton, P. A., Golec, J. M. C., & Pollard, J. R. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.573 · Cited by 633 · see citing works
Radiotherapy Promotes Tumor-Specific Effector CD8+ T Cells via Dendritic Cell Activation
Gupta, A. K., Probst, H. C., Vuong, V., Landshammer, A., Muth, S., Yagita∥, H., Schwendener, R. A., Pruschy, M. N., Knuth, A. K., & van den Broek, M. F. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1200563 · Cited by 446 · see citing works
Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice
de Klein, A., Muijtjens, M., van Os, R. P., Verhoeven, Y., Smit, B., Carr, A. M., Lehmann, A. R., & Hoeijmakers, J. H. J. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00447-4 · Cited by 437 · see citing works
Radiation Enhances Regulatory T Cell Representation
Kachikwu, E. L., Iwamoto, K. S., Liao, Y., DeMarco, J. J., Agazaryan, N., Economou, J. S., McBride, W. H., & Schaue, D. (2010) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2010.09.034 · Cited by 429 · see citing works
PD-1 expression on tumor-specific T cells: Friend or foe for immunotherapy?
Simon, S., & Labarrière, N. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1364828 · Cited by 399 · see citing works
Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma
Castle, J. C., Löewer, M., Boegel, S., de Graaf, J., Bender, C., Tadmor, A. D., Boisguérin, V., Bukur, T., Sorn, P., Paret, C., et al. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-190 · Cited by 386 · see citing works
Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice
Lau, J., Cheung, J., Navarro, A., Lianoglou, S., Haley, B., Tótpál, K., Sanders, L., Koeppen, H., Caplazi, P., McBride, J., et al. (2017) · Nature Communications · doi:10.1038/ncomms14572 · Cited by 365 · see citing works
Hypoxia Links ATR and p53 through Replication Arrest
Hammond, E. M., Denko, N. C., Dorie, M. J., Abraham, R. T., & Giaccia, A. J. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.6.1834-1843.2002 · Cited by 321 · see citing works
PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?
Xu-Monette, Z. Y., Zhang, M., Li, J., & Young, K. H. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01597 · Cited by 290 · see citing works
Hammond, E. M., Dorie, M. J., & Giaccia, A. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212360200 · Cited by 282 · see citing works
cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein.
Cimprich, K. A., Shin, T. B., Keith, C. T., & Schreiber, S. L. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.7.2850 · Cited by 273 · see citing works
Charrier, J., Durrant, S. J., Golec, J. M. C., Kay, D. P., Knegtel, R. M. A., MacCormick, S., Mortimore, M., O'Donnell, M. E., Pinder, J. L., Reaper, P. M., et al. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm101488z · Cited by 256 · see citing works
Hirahara, K., Ghoreschi, K., Yang, X., Takahashi, H., Laurence, A. D. J., Vahedi, G., Sciumè, G., Hall, A. O., Dupont, C. D., Francisco, L. M., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.03.024 · Cited by 253 · see citing works
Prevo, R., Fokas, E., Reaper, P. M., Charlton, P., Pollard, J. R., McKenna, W. G., Muschel, R. J., & Brunner, T. B. (2012) · Cancer Biology & Therapy · doi:10.4161/cbt.21093 · Cited by 242 · see citing works
Vendetti, F. P., Lau, A., Schamus, S., Conrads, T. P., O’Connor, M. J., & Bakkenist, C. J. (2015) · Oncotarget · doi:10.18632/oncotarget.6247 · Cited by 241 · see citing works
Self-citationPotentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970
Hall, A. B., Newsome, D., Wang, Y., Boucher, D. M., Eustace, B. K., Gu, Y., Hare, B. J., Johnson, M., Li, H. Y., Milton, S., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.2158 · Cited by 198 · see citing works
Targeting radiation-resistant hypoxic tumour cells through ATR inhibition
Pires, I. M., Olcina, M. M., Anbalagan, S., Pollard, J. R., Reaper, P. M., Charlton, P., McKenna, W. G., & Hammond, E. M. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.265 · Cited by 171 · see citing works
Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer
Herter-Sprie, G. S., Koyama, S., Korideck, H., Hai, J., Deng, J., Li, Y. Y., Buczkowski, K. A., Grant, A. K., Ullas, S., Rhee, K., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.87415 · Cited by 161 · see citing works
Saenz, S. A., Siracusa, M. C., Monticelli, L. A., et al. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20122332 · Cited by 133 · see citing works
Inhibition of ATR Leads to Increased Sensitivity to Hypoxia/Reoxygenation
Hammond, E. M., Dorie, M. J., & Giaccia, A. J. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1520 · Cited by 101 · see citing works
Tran, P. T., Shroff, E. H., Burns, T. F., Thiyagarajan, S., Das, S., Zabuawala, T., Chen, J., Cho, Y., Luong, R. H., Tamayo, P., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002650 · Cited by 99 · see citing works
Self-citationATR kinase activation in G1 phase facilitates the repair of ionizing radiation-induced DNA damage
Gamper, A. M., Rofougaran, R., Watkins, S. C., Greenberger, J. S., Beumer, J. H., & Bakkenist, C. J. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt833 · Cited by 69 · see citing works
Self-citationManipulating DNA damage-response signaling for the treatment of immune-mediated diseases
McNally, J. P., Millen, S. H., Chaturvedi, V., Lakes, N., Terrell, C. E., Elfers, E. E., Carroll, K. R., Hogan, S. P., Andreassen, P. R., Kanter, J., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1703683114 · Cited by 62 · see citing works
Vendetti, F. P., Leibowitz, B. J., Barnes, J., Schamus, S., Kiesel, B. F., Abberbock, S. R., Conrads, T. P., Clump, D. A., Cadogan, E. B., O’Connor, M. J., et al. (2017) · Scientific Reports · doi:10.1038/srep41892 · Cited by 20 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Immunological impact of cell death signaling driven by radiation on the tumor microenvironment
Rodriguez-Ruiz, M. E., Vitale, I., Harrington, K. J., Melero, I., & Galluzzi, L. (2020) · Nature Immunology · doi:10.1038/s41590-019-0561-4 · Cited by 385 · see citing works
Sheng, H., Huang, Y., Xiao, Y., Zhu, Z., Shen, M., Zhou, P., Guo, Z., Wang, J., Wang, H., Dai, W., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2019-000340 · Cited by 228 · see citing works
Immunomodulation by targeted anticancer agents
Petroni, G., Buqué, A., Zitvogel, L., Kroemer, G., & Galluzzi, L. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.11.009 · Cited by 212 · see citing works
Genomic instability, inflammatory signaling and response to cancer immunotherapy
Chen, M., Linstra, R., & van Vugt, M. A. T. M. (2022) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2021.188661 · Cited by 166 · see citing works
Deng, S., Vlatkovic, T., Li, M., Zhan, T., Veldwijk, M. R., & Herskind, C. (2022) · Cancers · doi:10.3390/cancers14194874 · Cited by 62 · see citing works
- Authors
- Vendetti, F. P., Karukonda, P., Clump, D. A., Teo, T., Lalonde, R., Nugent, K., Ballew, M., Kiesel, B. F., Beumer, J. H., Sarkar, S. N., Conrads, T. P., O’Connor, M. J., Ferris, R. L., Tran, P. T., Delgoffe, G. M., & Bakkenist, C. J.
- Affiliations
- University of Pittsburgh (US)
- Johns Hopkins University (US)
- Inova Health System (US)
- AstraZeneca (United Kingdom) (GB)
- Corresponding author
- Bakkenist, Christopher J.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-08-13
- Volume
- 128
- Issue
- 9
- Pages
- 3926-3940
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6118586
- OpenAlex
- W2810414233
- Cited by
- 198
- References
- 48
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 22 · 2023: 25 · 2022: 34 · 2021: 43 · 2020: 29 · 2019: 14 · 2018: 1
- FWCI
- 8.18
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH Office of the Director (R01CA204173, P50CA097190, R01CA166348, P30CA047904, as listed)
- Sidney Kimmel Foundation for Cancer Research (SKF-015-039)
- Stand Up To Cancer (SU2C-AACR-IRG-04-16)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- AZD6738, ATR inhibitors, CD8+ T cells, radiotherapy, PD-L1 upregulation, PD-1/PD-L1 axis, T cell exhaustion, regulatory T cells, KRAS-mutant cancer, immunological memory, combination immunotherapy, DNA damage signaling
- MeSH terms
- Adenocarcinoma of Lung, Animals, Humans, Indoles, Mice, Inbred BALB C, Morpholines, Neoplasms, Experimental, Pyrimidines, Sulfonamides, Sulfoxides, Colorectal Neoplasms, Lymphocytes, Tumor-Infiltrating, Proto-Oncogene Proteins p21(ras), CD8-Positive T-Lymphocytes, Radiotherapy, Conformal, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Chemoradiotherapy, B7-H1 Antigen, Ataxia Telangiectasia Mutated Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
