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Cited by 928Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Radiotherapy induces responses of lung cancer to CTLA-4 blockade

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Formenti, Silvia C., Rudqvist, Nils-Petter, Golden, Encouse, Cooper, Benjamin, Wennerberg, Erik, Lhuillier, Claire, Vanpouille-Box, Claire, Friedman, Kent +10 more·2018·Nature Medicine
DOI 10.1038/s41591-018-0232-2PMC PMC6286242
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Abstract

Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma 1-3, but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor 4-6. The latter is essential for achieving abscopal responses in murine cancers 6. The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy 7,8. Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-β after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system.

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  • Compelling clinical and experimental evidence support the importance of IFN-β production by tumor cells themselves in mediating antitumor responses to radiation therapy in combination with immune checkpoint inhibitors.

    “Nevertheless, compelling clinical and experimental evidence support the importance of IFN-β production by tumor cells themselves in mediating antitumor responses to radiation therapy in combination with immune checkpoint inhibitors46–48.”

    From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [48]

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  1. [1]Formenti SC & Demaria S Systemic effects of local radiotherapy. Lancet Oncol 10, 718– 726 (2009). 19573801 PMC2782943
  2. [2]Demaria S, Coleman CN & Formenti SC Radiotherapy: Changing the Game in Immunotherapy. Trends Cancer 2, 286– 294 (2016). 27774519 PMC5070800
  3. [3]Postow MA, Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366, 925– 931 (2012). 22397654 PMC3345206
  4. [4]Burnette BC, The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res 71, 2488– 2496 (2011). 21300764 PMC3070872
  5. [5]Deng L, STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. Immunity 41, 843– 852 (2014). 25517616 PMC5155593
  6. [6]Vanpouille-Box C, DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun 8, 15618 (2017). PMC5472757 28598415
  7. [7]Zatloukal P, Randomized phase II clinical trial comparing tremelimumab (CP-675, 206) with best supportive care (BSC) following first-line platinum-based therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 27, 8071 (2009).
  8. [8]Lynch TJ, Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol 30, 2046– 2054 (2012). 22547592
  9. [9]Golden EB, Demaria S, Schiff PB, Chachoua A & Formenti SC An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 1, 365– 372 (2013). 24563870 PMC3930458
  10. [10]Golden EB, Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol 16, 795– 803 (2015). 26095785
  11. [12]Gainor JF, EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis. Clin Cancer Res 22, 4585– 4593 (2016). 27225694 PMC5026567
  12. [13]Ng Tang D, Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer Immunol Res 1, 229– 234 (2013). 24777852 PMC4636341
  13. [14]Wang W, Biomarkers on melanoma patient T cells associated with ipilimumab treatment. J Transl Med 10, 146 (2012). 22788688 PMC3527361
  14. [15]Sim GC, IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. J Clin Invest 124, 99– 110 (2014). 24292706 PMC3871216
  15. [16]Kuo P, Galectin-1 mediates radiation-related lymphopenia and attenuates NSCLC radiation response. Clin Cancer Res 20, 5558– 5569 (2014). 25189484 PMC4216761
  16. [17]Koguchi Y, Serum Immunoregulatory Proteins as Predictors of Overall Survival of Metastatic Melanoma Patients Treated with Ipilimumab. Cancer Res 75, 5084– 5092 (2015). 26627641
  17. [18]Jinushi M, Hodi FS & Dranoff G Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. Proc Natl Acad Sci U S A 103, 9190– 9195 (2006). 16754847 PMC1482588
  18. [19]Ferrari de Andrade L, Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell–driven tumor immunity. Science In press(2018). PMC6626532 29599246
  19. [20]Gasser S, Orsulic S, Brown EJ & Raulet DH The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186– 1190 (2005). 15995699 PMC1352168
  20. [21]Ruocco MG, Suppressing T cell motility induced by anti-CTLA-4 monotherapy improves antitumor effects. J Clin Invest 122, 3718– 3730 (2012). 22945631 PMC3461908
  21. [22]Rudqvist NP, Radiotherapy and CTLA-4 Blockade Shape the TCR Repertoire of Tumor-Infiltrating T Cells. Cancer Immunol Res 6, 139– 150 (2018). 29180535 PMC6020019
  22. [23]Sidhom JW, ImmunoMap: A Bioinformatics Tool for T-cell Repertoire Analysis. Cancer Immunol Res 6, 151– 162 (2018). 29263161 PMC6478441
  23. [25]Snyder A, Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371, 2189– 2199 (2014). 25409260 PMC4315319
  24. [27]Sharma P, Hu-Lieskovan S, Wargo JA & Ribas A Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell 168, 707– 723 (2017). 28187290 PMC5391692
  25. [28]Song KH, Induction of immunogenic cell death by radiation-upregulated karyopherin alpha 2 in vitro. Eur J Cell Biol 95, 219– 227 (2016). 27107455
  26. [29]Twyman-Saint Victor C, Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373– 377 (2015). 25754329 PMC4401634
  27. [30]Harding SM, Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466– 470 (2017). 28759889 PMC5857357
  28. [31]Konno H, Suppression of STING signaling through epigenetic silencing and missense mutation impedes DNA damage mediated cytokine production. Oncogene 37, 2037– 2051 (2018). 29367762 PMC6029885
  29. [33]Wolchok JD, Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15, 7412– 7420 (2009). 19934295
  30. [34]Formenti SC, Results of a phase I-II study of adjuvant concurrent carboplatin and accelerated radiotherapy for triple negative breast cancer. Oncoimmunology 6, e1274479 (2017). 28405497 PMC5384379
  31. [35]Carlson CS, Using synthetic templates to design an unbiased multiplex PCR assay. Nat Commun 4, 2680 (2013). 24157944
  32. [36]Yousfi Monod M, Giudicelli V, Chaume D & Lefranc MP IMGT/JunctionAnalysis: the first tool for the analysis of the immunoglobulin and T cell receptor complex V-J and V-D-J JUNCTIONs. Bioinformatics 20 Suppl 1, i379– 385 (2004). 15262823
  33. [37]Wu D, Detection of minimal residual disease in B lymphoblastic leukemia by high-throughput sequencing of IGH. Clin Cancer Res 20, 4540– 4548 (2014). 24970842 PMC5142743
  34. [38]Sherwood AM, Tumor-infiltrating lymphocytes in colorectal tumors display a diversity of T cell receptor sequences that differ from the T cells in adjacent mucosal tissue. Cancer immunology, immunotherapy: CII 62, 1453– 1461 (2013). 23771160 PMC5714653
  35. [39]DeWitt WS, Dynamics of the cytotoxic T cell response to a model of acute viral infection. J Virol 89, 4517– 4526 (2015). 25653453 PMC4442358
  36. [41]Schliep KP phangorn: phylogenetic analysis in R. Bioinformatics 27, 592– 593 (2011). 21169378 PMC3035803
  37. [45]Tang F & Ishwaran H Random forest missing data algorithms. Statistical Analysis and Data Mining: The ASA Data Science Journal 10, 363– 377 (2017). PMC5796790 29403567
  38. [47]Li, H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv preprint arXiv:1303.3997 (2013). · arXiv
  39. [48]McKenna A, The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20, 1297– 1303 (2010). 20644199 PMC2928508
  40. [49]Koboldt DC, VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res 22, 568– 576 (2012). 22300766 PMC3290792
  41. [53]Szolek A, OptiType: precision HLA typing from next-generation sequencing data. Bioinformatics 30, 3310– 3316 (2014). 25143287 PMC4441069
  42. [54]McLaren W, The Ensembl Variant Effect Predictor. Genome Biol 17, 122 (2016). 27268795 PMC4893825
  43. [55]Hundal J, pVAC-Seq: A genome-guided in silico approach to identifying tumor neoantigens. Genome Med 8, 11 (2016). 26825632 PMC4733280
  44. [56]Nielsen M, Reliable prediction of T-cell epitopes using neural networks with novel sequence representations. Protein Sci 12, 1007– 1017 (2003). 12717023 PMC2323871
  45. [57]Andreatta M & Nielsen M Gapped sequence alignment using artificial neural networks: application to the MHC class I system. Bioinformatics 32, 511– 517 (2016). 26515819 PMC6402319

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Authors
Formenti, S. C., Rudqvist, N.-P., Golden, E., Cooper, B., Wennerberg, E., Lhuillier, C., Vanpouille-Box, C., Friedman, K., Ferrari de Andrade, L., Wucherpfennig, K. W., Heguy, A., Imai, N., Gnjatic, S., Emerson, R. O., Zhou, X. K., Zhang, T., Chachoua, A., & Demaria, S.
Affiliations
  • Weill Cornell Medicine (US)
  • University of California, San Francisco (US)
  • New York University (US)
  • Harvard University (US)
  • NYU Langone Health (US)
  • Tisch Cancer Institute (US)
  • Adaptive Biotechnologies (United States) (US)
Corresponding author
  • Formenti, Silvia C.
  • Demaria, Sandra
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2018-11-05
Volume
24
Issue
12
Pages
1845-1851
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-018-0232-2
PMC
PMC6286242
OpenAlex
W2898394368
Cited by
928
References
8
Citations by year
2026: 70 · 2025: 101 · 2024: 138 · 2023: 136 · 2022: 120 · 2021: 153 · 2020: 141 · 2019: 62 · 2018: 7
FWCI
34.11
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA198533, R01CA173750, R01CA201246, P30CA016087, P30CA196521)
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
radiotherapy, CTLA-4 blockade, abscopal effect, non-small cell lung cancer, type I interferon, interferon-beta, antitumor T cells, CD8+ T cells, neoantigens, predictive biomarkers, immune checkpoint inhibitors
MeSH terms
Ipilimumab, Aged, Aged, 80 and over, Antibodies, Monoclonal, Combined Modality Therapy, Female, Humans, Lung Neoplasms, Male, Middle Aged, Radiotherapy, CD8-Positive T-Lymphocytes, Drug Resistance, Neoplasm, Cell Line, Tumor, CTLA-4 Antigen

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