CoChat
Sign Up
Cited by 128CAR-T cell therapy researchVirus-based gene therapy researchImmunotherapy and Immune Responses

Oncolytic virus-derived type I interferon restricts CAR T cell therapy

Open access
Evgin, Laura, Huff, Amanda L., Wongthida, Phonphimon, Thompson, Jill, Kottke, Tim, Tonne, Jason, Schuelke, Matthew, Ayasoufi, Katayoun +12 more·2020·Nature Communications
DOI 10.1038/s41467-020-17011-zPMC PMC7314766
Open this paper in CoChat — free accountOpen PDF

Abstract

The application of adoptive T cell therapies, including those using chimeric antigen receptor (CAR)-modified T cells, to solid tumors requires combinatorial strategies to overcome immune suppression associated with the tumor microenvironment. Here we test whether the inflammatory nature of oncolytic viruses and their ability to remodel the tumor microenvironment may help to recruit and potentiate the functionality of CAR T cells. Contrary to our hypothesis, VSVmIFNβ infection is associated with attrition of murine EGFRvIII CAR T cells in a B16EGFRvIII model, despite inducing a robust proinflammatory shift in the chemokine profile. Mechanistically, type I interferon (IFN) expressed following infection promotes apoptosis, activation, and inhibitory receptor expression, and interferon-insensitive CAR T cells enable combinatorial therapy with VSVmIFNβ. Our study uncovers an unexpected mechanism of therapeutic interference, and prompts further investigation into the interaction between CAR T cells and oncolytic viruses to optimize combination therapy.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-020-17011-z

Cites

7 of 7 references verified0 citation errors · 0 not checkable

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.

A few free checks a day · papers already verified open instantly · results are public

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?

  • IFN-β was reported to cause pronounced attrition of CAR T cells, leading to inferior survival of tumor-bearing mice treated with CAR T cells and IFN-β.

    “Moreover, IFN-β was reported to cause pronounced attrition of CAR T cells, leading to inferior survival of tumor-bearing mice treated with CAR T cells and IFN-β [28].”

    From Ectopic PU.1 Expression Provides Chimeric Antigen Receptor (CAR) T Cells with Innate Cell Capacities Including IFN-β Release (2024) · cites this paper as [28]

    The Results sections ‘Type I IFN is deleterious to CAR T cells’ and ‘IFNβ elicits T cell intrinsic and CAR T specific effects’ link virus-associated IFNβ to CAR T-cell attrition and show that recombinant IFNβ increases CAR T-cell apoptosis. But ‘Combination therapy does not provide superior tumor control’ reports no improvement in survival with VSVmIFNβ plus CAR T cells, not inferior survival relative to CAR T cells alone. The mouse treatment also used an IFNβ-expressing virus, rather than IFNβ administered alone. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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

Flagged first, then by citations

Research works printed but not linked: 48

  1. [2]Maude SL Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia N. Engl. J. Med. 2018 378 439 448 29385370 PMC5996391
  2. [3]Newick K O’Brien S Moon E Albelda SM CAR T cell therapy for solid tumors Annu. Rev. Med. 2017 68 139 152 27860544
  3. [4]Stojdl DF VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents Cancer Cell 2003 4 263 275 14585354
  4. [5]Prestwich RJ Reciprocal human dendritic cell-natural killer cell interactions induce antitumor activity following tumor cell infection by oncolytic reovirus J. Immunol. 2009 183 4312 4321 19734207
  5. [6]Steele L Pro-inflammatory cytokine/chemokine production by reovirus treated melanoma cells is PKR/NF-kappaB mediated and supports innate and adaptive anti-tumour immune priming Mol. Cancer 2011 10 20 21338484 PMC3052210
  6. [7]Ribas A Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy Cell 2017 170 1109 1119 e1110 28886381 PMC8034392
  7. [8]Lang FF Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma J. Clin. Oncol. 2018 36 1419 1427 29432077 PMC6075856
  8. [9]Twumasi-Boateng K Pettigrew JL Kwok YYE Bell JC Nelson BH Oncolytic viruses as engineering platforms for combination immunotherapy Nat. Rev. Cancer 2018 18 419 432 29695749
  9. [10]Nishio N Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors Cancer Res. 2014 74 5195 5205 25060519 PMC4167556
  10. [11]Wing A Improving CART-cell therapy of solid tumors with oncolytic virus-driven production of a bispecific T-cell engager Cancer Immunol. Res 2018 6 605 616 29588319 PMC6688490
  11. [12]Rosewell Shaw A Adenovirotherapy delivering cytokine and checkpoint inhibitor augments CAR T Cells against metastatic head and neck cancer Mol. Ther. 2017 25 2440 2451 28974431 PMC5675597
  12. [13]Tanoue K Armed oncolytic adenovirus-expressing PD-L1 mini-body enhances antitumor effects of chimeric antigen receptor T cells in solid tumors Cancer Res. 2017 77 2040 2051 28235763 PMC5392365
  13. [14]Stojdl DF Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus Nat. Med 2000 6 821 825 10888934
  14. [15]Obuchi M Fernandez M Barber GN Development of recombinant vesicular stomatitis viruses that exploit defects in host defense to augment specific oncolytic activity J. Virol. 2003 77 8843 8856 12885903 PMC167243
  15. [16]Willmon CL Expression of IFN-beta enhances both efficacy and safety of oncolytic vesicular stomatitis virus for therapy of mesothelioma Cancer Res. 2009 69 7713 7720 19773437 PMC3891512
  16. [17]Welsh RM Bahl K Marshall HD Urban SL Type 1 interferons and antiviral CD8 T-cell responses PLoS Pathog. 2012 8 e1002352 22241987 PMC3252364
  17. [19]Keppler SJ Rosenits K Koegl T Vucikuja S Aichele P Signal 3 cytokines as modulators of primary immune responses during infections: the interplay of type I IFN and IL-12 in CD8 T cell responses PLoS ONE 2012 7 e40865 22815848 PMC3398954
  18. [20]Jenks N Safety studies on intrahepatic or intratumoral injection of oncolytic vesicular stomatitis virus expressing interferon-beta in rodents and nonhuman primates Hum. Gene Ther. 2010 21 451 462 19911974 PMC2865219
  19. [21]Sampson JH EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss Clin. Cancer Res. 2014 20 972 984 24352643 PMC3943170
  20. [22]Crouse J Kalinke U Oxenius A Regulation of antiviral T cell responses by type I interferons Nat. Rev. Immunol. 2015 15 231 242 25790790
  21. [23]Bahl K Huebner A Davis RJ Welsh RM Analysis of apoptosis of memory T cells and dendritic cells during the early stages of viral infection or exposure to toll-like receptor agonists J. Virol. 2010 84 4866 4877 20200235 PMC2863811
  22. [24]Bahl K IFN-induced attrition of CD8 T cells in the presence or absence of cognate antigen during the early stages of viral infections J. Immunol. 2006 176 4284 4295 16547266
  23. [25]Jangalwe S Cutting edge: early attrition of memory T cells during inflammation and costimulation blockade is regulated concurrently by proapoptotic proteins Fas and Bim J. Immunol. 2019 202 647 651 30610162 PMC6344249
  24. [26]Crouse J Type I interferons protect T cells against NK cell attack mediated by the activating receptor NCR1 Immunity 2014 40 961 973 24909889
  25. [27]Xu HC Type I interferon protects antiviral CD8+ T cells from NK cell cytotoxicity Immunity 2014 40 949 960 24909887
  26. [28]Long AH 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors Nat. Med. 2015 21 581 590 25939063 PMC4458184
  27. [29]Gomes-Silva D Tonic 4-1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent Cell Rep. 2017 21 17 26 28978471 PMC5645034
  28. [30]Morgan RA Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma Hum. Gene Ther. 2012 23 1043 1053 22780919 PMC3472555
  29. [31]Kolumam GA Thomas S Thompson LJ Sprent J Murali-Krishna K Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection J. Exp. Med. 2005 202 637 650 16129706 PMC2212878
  30. [32]Amos SM Adoptive immunotherapy combined with intratumoral TLR agonist delivery eradicates established melanoma in mice Cancer Immunol. Immunother. 2011 60 671 683 21327636 PMC3499620
  31. [33]Huber JP Farrar JD Regulation of effector and memory T-cell functions by type I interferon Immunology 2011 132 466 474 21320124 PMC3075500
  32. [34]Harari D Bridging the species divide: transgenic mice humanized for type-I interferon response PLoS ONE 2014 9 e84259 24416207 PMC3887009
  33. [35]de Weerd NA A hot spot on interferon alpha/beta receptor subunit 1 (IFNAR1) underpins its interaction with interferon-beta and dictates signaling J. Biol. Chem. 2017 292 7554 7565 28289093 PMC5418053
  34. [36]Colamonici OR Domanski P Sweitzer SM Larner A Buller RM Vaccinia virus B18R gene encodes a type I interferon-binding protein that blocks interferon alpha transmembrane signaling J. Biol. Chem. 1995 270 15974 15978 7608155
  35. [37]Le Boeuf F Synergistic interaction between oncolytic viruses augments tumor killing Mol. Ther. 2010 18 888 895 20234341 PMC2890112
  36. [38]Moon EK Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines Oncoimmunology 2018 7 e1395997 29399394 PMC5790399
  37. [41]Zhao Z Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T Cells Cancer Cell 2015 28 415 428 26461090 PMC5003056
  38. [42]Haanen J Converting cold into hot tumors by combining immunotherapies Cell 2017 170 1055 1056 28886376
  39. [43]Ishizuka JJ Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade Nature 2019 565 43 48 30559380 PMC7241251
  40. [44]Senior M Checkpoint inhibitors go viral Nat. Biotechnol. 2019 37 12 17 30605149
  41. [45]Samson, A. et al. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci. Transl. Med.10, eaam7577 (2018). PMC6276984 29298869
  42. [46]Bommareddy, P. K., Aspromonte, S., Zloza, A., Rabkin, S. D. & Kaufman, H. L. MEK inhibition enhances oncolytic virus immunotherapy through increased tumor cell killing and T cell activation. Sci. Transl. Med.10, eaau0417 (2018). PMC7593827 30541787
  43. [47]Chen CY Hutzen B Wedekind MF Cripe TP Oncolytic virus and PD-1/PD-L1 blockade combination therapy Oncolytic Virother 2018 7 65 77 30105219 PMC6074764
  44. [51]Suryadevara CM Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma Oncoimmunology 2018 7 e1434464 29872570 PMC5980382
  45. [52]Gedeon PC A rationally designed fully human EGFRvIII:CD3-targeted bispecific antibody redirects human T cells to treat patient-derived intracerebral malignant glioma Clin. Cancer Res. 2018 24 3611 3631 29703821 PMC6103776
  46. [53]Riccione, K. et al. Generation of CAR T cells for adoptive therapy in the context of glioblastoma standard of care. J. Vis. Exp.96, e52397 (2015). PMC4354646 25741761
  47. [54]Dietz AB A novel source of viable peripheral blood mononuclear cells from leukoreduction system chambers Transfusion 2006 46 2083 2089 17176319
  48. [55]Zheng Z Chinnasamy N Morgan RA Protein L: a novel reagent for the detection of chimeric antigen receptor (CAR) expression by flow cytometry J. Transl. Med. 2012 10 29 22330761 PMC3299624

Cited by

Sorted by citations

Authors
Evgin, L., Huff, A. L., Wongthida, P., Thompson, J., Kottke, T., Tonne, J., Schuelke, M., Ayasoufi, K., Driscoll, C. B., Shim, K. G., Reynolds, P., Monie, D. D., Johnson, A. J., Coffey, M., Young, S. L., Archer, G., Sampson, J., Pulido, J., Perez, L. S., & Vile, R.
Affiliations
  • Mayo Clinic (US)
  • Oncolytics Biotech (Canada) (CA)
  • University of Otago (NZ)
  • Duke University (US)
Corresponding author
Vile, Richard
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-06-24
Volume
11
Issue
1
Pages
3187-3187
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-17011-z
PMC
PMC7314766
OpenAlex
W3037602706
Cited by
128
References
7
Citations by year
2026: 23 · 2025: 20 · 2024: 27 · 2023: 20 · 2022: 21 · 2021: 13 · 2020: 4
FWCI
5.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | National Institutes of Health (R01 CA175386, R01 CA108961)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
oncolytic viruses, type I interferon, CAR T-cell therapy, EGFRvIII, tumor microenvironment, T cell apoptosis, inhibitory receptors, chemokine profile, combination therapy, adoptive T cell therapy
MeSH terms
Receptors, Chimeric Antigen, Animals, Combined Modality Therapy, Female, Lymphocyte Activation, Melanoma, Experimental, Mice, Inbred C57BL, Mice, Mutant Strains, Receptors, Antigen, T-Cell, Spleen, T-Lymphocytes, Immunotherapy, Adoptive, Interferon-beta, Apoptosis, Chemokines, Cell Line, Tumor, Oncolytic Virotherapy, Oncolytic Viruses, Mice, Receptor, Interferon alpha-beta

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