Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses

Nature Medicine volume 22, pages 1402–1410 (2016)Cite this article

Subjects

Abstract

Checkpoint blockade with antibodies specific for cytotoxic T lymphocyte–associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD-1) elicits durable tumor regression in metastatic cancer, but these dramatic responses are confined to a minority of patients. This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint. Here we describe a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse model of melanoma; to our knowledge tumors of this size have not previously been curable by treatments relying on endogenous immunity. Maximal antitumor efficacy required four components: a tumor-antigen-targeting antibody, a recombinant interleukin-2 with an extended half-life, anti-PD-1 and a powerful T cell vaccine. Depletion experiments revealed that CD8+ T cells, cross-presenting dendritic cells and several other innate immune cell subsets were required for tumor regression. Effective treatment induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake and promoted antigen spreading. These results demonstrate the capacity of an elicited endogenous immune response to destroy large, established tumors and elucidate essential characteristics of combination immunotherapies that are capable of curing a majority of tumors in experimental settings typically viewed as intractable.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: AIPV immunotherapy cures large established tumors and establishes protective memory in multiple tumor models.
Figure 2: AIPV therapy primes sustained vaccine-specific T cell responses and remodels the microenvironment of established tumors.
Figure 3: AIPV therapy induces pronounced immune infiltration of tumors with efficacy dependent on innate and adaptive immune cells.
Figure 4: Combination therapy elicits antibody-enhanced antigen spreading and de novo T cell responses.
Figure 5: AIPV therapy induces de novo endogenous tumor-specific antibody responses.
Figure 6: AIPV with a trivalent vaccine is curative for established B16F10 tumors and induces regression in Braf/Pten autochthonous melanoma.

Similar content being viewed by others

References

  1. Hodi, F.S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Topalian, S.L. et al. Safety, activity and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    PubMed  PubMed Central  Google Scholar 

  4. Gajewski, T.F. The next hurdle in cancer immunotherapy: overcoming the non-T-cell-inflamed tumor microenvironment. Semin. Oncol. 42, 663–671 (2015).

    PubMed  PubMed Central  Google Scholar 

  5. Zou, W., Wolchok, J.D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers and combinations. Sci. Transl. Med. 8, 328rv4 (2016).

    PubMed  PubMed Central  Google Scholar 

  6. Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Drake, C.G. Combination immunotherapy approaches. Ann. Oncol. 23 (Suppl. 8), 41–46 (2012).

    Google Scholar 

  8. Sharma, P. & Allison, J.P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    CAS  PubMed  Google Scholar 

  9. Smyth, M.J., Ngiow, S.F., Ribas, A. & Teng, M.W.L. Combination cancer immunotherapies tailored to the tumor microenvironment. Nat. Rev. Clin. Oncol. 13, 143–158 (2016).

    CAS  PubMed  Google Scholar 

  10. Curran, M.A., Kim, M., Montalvo, W., Al-Shamkhani, A. & Allison, J.P. Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T cell infiltration, proliferation and cytokine production. PLoS One 6, e19499 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Carmi, Y. et al. Allogeneic IgG combined with dendritic cell stimuli induce antitumor T cell immunity. Nature 521, 99–104 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hu-Lieskovan, S. et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma. Sci. Transl. Med. 7, 279ra41 (2015).

    PubMed  PubMed Central  Google Scholar 

  13. Rapoport, A.P. et al. Combination immunotherapy after ASCT for multiple myeloma using MAGE-A3–poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and co-stimulated autologous T cells. Clin. Cancer Res. 20, 1355–1365 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lum, L.G. et al. Targeted T cell therapy in stage IV breast cancer: a phase 1 clinical trial. Clin. Cancer Res. 21, 2305–2314 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ribas, A. et al. Phase 1 study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. ASCO Annual Meeting Proceedings 33, abstract 3003 (American Society of Clinical Oncology, Alexandria, Virginia, USA, 2015).

    Google Scholar 

  16. Chen, G. et al. A feasibility study of cyclophosphamide, trastuzumab and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer. Cancer Immunol. Res. 2, 949–961 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Overwijk, W.W. et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J. Exp. Med. 198, 569–580 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Klebanoff, C.A. et al. Determinants of successful CD8+ T cell adoptive immunotherapy for large established tumors in mice. Clin. Cancer Res. 17, 5343–5352 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. DuPage, M. et al. Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. Cancer Cell 19, 72–85 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Stromnes, I.M. et al. T cells engineered against a native antigen can surmount immunologic and physical barriers to treat pancreatic ductal adenocarcinoma. Cancer Cell 28, 638–652 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhu, E.F. et al. Synergistic innate and adaptive immune response to combination immunotherapy with anti-tumor-antigen antibodies and extended serum half-life IL-2. Cancer Cell 27, 489–501 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu, H. et al. Structure-based programming of lymph node targeting in molecular vaccines. Nature 507, 519–522 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Moore, S.J. et al. Engineered knottin peptide enables non-invasive optical imaging of intracranial medulloblastoma. Proc. Natl. Acad. Sci. USA 110, 14598–14603 (2013).

    CAS  PubMed  Google Scholar 

  24. Phan, G.Q., Attia, P., Steinberg, S.M., White, D.E. & Rosenberg, S.A. Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J. Clin. Oncol. 19, 3477–3482 (2001).

    CAS  PubMed  Google Scholar 

  25. Rose, S., Misharin, A. & Perlman, H. A novel Ly6C- and Ly6G-based strategy to analyze the mouse splenic myeloid compartment. Cytometry A 81, 343–350 (2012).

    PubMed  Google Scholar 

  26. Ostrand-Rosenberg, S. & Sinha, P. Myeloid-derived suppressor cells: linking inflammation and cancer. J. Immunol. 182, 4499–4506 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8-α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Rafiq, K., Bergtold, A. & Clynes, R. Immune-complex-mediated antigen presentation induces tumor immunity. J. Clin. Invest. 110, 71–79 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Broz, M.L. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 638–652 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Roberts, E.W. et al. Critical role for CD103+/CD141+ dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 30, 324–336 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Salmon, H. et al. Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44, 924–938 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Dankort, D. et al. BrafV600E cooperates with Pten loss to induce metastatic melanoma. Nat. Genet. 41, 544–552 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Mendiratta, S.K. et al. Therapeutic tumor immunity induced by polyimmunization with melanoma antigens gp100 and TRP-2. Cancer Res. 61, 859–863 (2001).

    CAS  PubMed  Google Scholar 

  34. Nelson, M.H. et al. Toll-like receptor agonist therapy can profoundly augment the antitumor activity of adoptively transferred CD8+ T cells without host preconditioning. J. Immunother. Cancer 4, 6 (2016).

    PubMed  PubMed Central  Google Scholar 

  35. Woo, S.R., Corrales, L. & Gajewski, T.F. Innate immune recognition of cancer. Annu. Rev. Immunol. 33, 445–474 (2015).

    CAS  PubMed  Google Scholar 

  36. van Egmond, M. & Bakema, J.E. Neutrophils as effector cells for antibody-based immunotherapy of cancer. Semin. Cancer Biol. 23, 190–199 (2013).

    CAS  PubMed  Google Scholar 

  37. Weiskopf, K. & Weissman, I.L. Macrophages are critical effectors of antibody therapies for cancer. MAbs 7, 303–310 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. DiLillo, D.J. & Ravetch, J.V. Differential Fc receptor engagement drives an antitumor vaccinal effect. Cell 161, 1035–1045 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. van Montfoort, N. et al. Antigen storage compartments in mature dendritic cells facilitate prolonged cytotoxic T lymphocyte cross-priming capacity. Proc. Natl. Acad. Sci. USA 106, 6730–6735 (2009).

    CAS  PubMed  Google Scholar 

  40. Guilliams, M., Bruhns, P., Saeys, Y., Hammad, H. & Lambrecht, B.N. The function of Fc-γ receptors in dendritic cells and macrophages. Nat. Rev. Immunol. 14, 94–108 (2014).

    CAS  PubMed  Google Scholar 

  41. Clatworthy, M.R. et al. Immune complexes stimulate CCR7-dependent dendritic cell migration to lymph nodes. Nat. Med. 20, 1458–1463 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Albanesi, M. et al. Neutrophils mediate antibody-induced antitumor effects in mice. Blood 122, 3160–3164 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Allan, R.S. et al. Migratory dendritic cells transfer antigen to a lymph-node-resident dendritic cell population for efficient CTL priming. Immunity 25, 153–162 (2006).

    CAS  PubMed  Google Scholar 

  44. den Haan, J.M., Lehar, S.M. & Bevan, M.J. CD8+ but not CD8− dendritic cells cross-prime cytotoxic T cells in vivo. J. Exp. Med. 192, 1685–1696 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Gasteiger, G. et al. IL-2-dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells. J. Exp. Med. 210, 1167–1178 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. List, J. et al. Cytokine responses to intraventricular injection of interleukin-2 into patients with leptomeningeal carcinomatosis: rapid induction of tumor necrosis factor–α, interleukin 1–β, interleukin-6, γ-interferon and soluble interleukin-2 receptor (Mr 55,000 protein). Cancer Res. 52, 1123–1128 (1992).

    CAS  PubMed  Google Scholar 

  47. Carreno, B.M. et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348, 803–808 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. DuPage, M., Mazumdar, C., Schmidt, L.M., Cheung, A.F. & Jacks, T. Expression of tumor-specific antigens underlies cancer immuno-editing. Nature 482, 405–409 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Vigneron, N., Stroobant, V., Van den Eynde, B.J. & van der Bruggen, P. Database of T cell–defined human tumor antigens: the 2013 update. Cancer Immun. 13, 15 (2013).

    PubMed  PubMed Central  Google Scholar 

  50. Yadav, M. et al. Predicting immunogenic tumor mutations by combining mass spectrometry and exome sequencing. Nature 515, 572–576 (2014).

    CAS  PubMed  Google Scholar 

  51. Gubin, M.M. et al. Checkpoint blockade cancer immunotherapy targets tumor-specific mutant antigens. Nature 515, 577–581 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Desgrosellier, J.S. & Cheresh, D.A. Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 10, 9–22 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Morgan, R.A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Johnson, L.A. et al. Gene therapy with human and mouse T cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114, 535–546 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Tzeng, A., Kwan, B.H., Opel, C.F., Navaratna, T. & Wittrup, K.D. Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution. Proc. Natl. Acad. Sci. USA 112, 3320–3325 (2015).

    CAS  PubMed  Google Scholar 

  56. Boggio, K. et al. Interleukin-12-mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice. J. Exp. Med. 188, 589–596 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Guevara-Patiño, J.A. et al. Optimization of a self-antigen for presentation of multiple epitopes in cancer immunity. J. Clin. Invest. 116, 1382–1390 (2006).

    PubMed  PubMed Central  Google Scholar 

  58. van Stipdonk, M.J.B. et al. Design of agonistic altered peptides for the robust induction of CTL directed towards H-2Db in complex with the melanoma-associated epitope gp100. Cancer Res. 69, 7784–7792 (2009).

    CAS  PubMed  Google Scholar 

  59. Malakhov, M.P. et al. SUMO fusions and SUMO-specific protease for efficient expression and purification of proteins. J. Struct. Funct. Genomics 5, 75–86 (2004).

    CAS  PubMed  Google Scholar 

  60. Rubinstein, M.P. et al. Converting IL-15 to a superagonist by binding to soluble IL-15Rα. Proc. Natl. Acad. Sci. USA 103, 9166–9171 (2006).

    CAS  PubMed  Google Scholar 

  61. Hooijkaas, A.I., Gadiot, J., van der Valk, M., Mooi, W.J. & Blank, C.U. Targeting BRAFV600E in an inducible murine model of melanoma. Am. J. Pathol. 181, 785–794 (2012).

    CAS  PubMed  Google Scholar 

  62. Muzumdar, M.D., Tasic, B., Miyamichi, K., Li, L. & Luo, L. A global double-fluorescent Cre reporter mouse. Genesis 45, 593–605 (2007).

    CAS  PubMed  Google Scholar 

  63. Chen, B. et al. Dynamic imaging of genomic loci in living human cells by an optimized CRISPR–Cas system. Cell 155, 1479–1491 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Joshi, N.S. et al. Regulatory T cells in tumor-associated tertiary lymphoid structures suppress antitumor T cell responses. Immunity 43, 579–590 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, the US National Institutes of Health (NIH) grant CA174795 (K.D.W.), the Bridge Project partnership between the Koch Institute for Integrative Cancer Research and the Dana Farber–Harvard Cancer Center (DF–HCC) (D.J.I.), the V Foundation (D.J.I.) and the Ragon Institute (D.J.I.). K.D.M. and J.M.E. are supported by the Fannie and John Hertz Foundation Fellowship; K.D.M., C.F.O., J.M.E., B.H.K. and E.F.Z. are supported by NSF Graduate Research Fellowships; A.M.R. is supported by the NIGMS–NIH Interdepartmental Biotechnology Training Program (NIH #T32GM008334); A.T. is supported by the Siebel Scholarship; and G.L.S. was supported by the NIH with a Ruth L. Kirschstein National Research Service Award (CA180586). We thank T.C. Wu (Johns Hopkins University) for kindly providing the TC-1 tumor cells, D. Sabatini (Whitehead Institute) for providing the Cas9 constructs and G. Dranoff (Dana-Farber Cancer Institute) for providing the DD-Her2/neu and B16-OVA cells. We thank M. Ghebremichael (Ragon Institute of MGH, MIT and Harvard) for helpful statistical advice. We thank the Koch Institute Swanson Biotechnology Center for technical support, specifically the applied therapeutics and whole-animal imaging core facility, the histology and the flow cytometry core facilities. D.J.I. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Gregory L Szeto & Michael H Zhang

    Present address: Present address: Department of Chemical, Biochemical and Environmental Engineering, University of Maryland Baltimore, Baltimore, Maryland, USA.,

  2. Kelly D Moynihan and Cary F Opel: These authors contributed equally to this work.

Authors and Affiliations

  1. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA

    Kelly D Moynihan, Cary F Opel, Gregory L Szeto, Alice Tzeng, Eric F Zhu, Kavya Rakhra, Michael H Zhang, Adrienne M Rothschilds, Sudha Kumari, Ryan L Kelly, Byron H Kwan, Wuhbet Abraham, Naveen K Mehta, Monique J Kauke, Heikyung Suh, Douglas A Lauffenburger, K Dane Wittrup & Darrell J Irvine

  2. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Kelly D Moynihan, Gregory L Szeto, Alice Tzeng, Adrienne M Rothschilds, Ryan L Kelly, Byron H Kwan, Kevin Hu, Naveen K Mehta, Douglas A Lauffenburger, K Dane Wittrup & Darrell J Irvine

  3. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA

    Kelly D Moynihan, Gregory L Szeto, Douglas A Lauffenburger & Darrell J Irvine

  4. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Cary F Opel, Eric F Zhu, Monique J Kauke & K Dane Wittrup

  5. Division of Health, Science and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Jesse M Engreitz

  6. The Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA

    Jesse M Engreitz

  7. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Robert T Williams

  8. Department of Bioengineering, Stanford University, Stanford, California, USA

    Jennifer R Cochran

  9. Department of Chemical Engineering, Stanford University, Stanford, California, USA

    Jennifer R Cochran

  10. Stanford Cancer Institute, Stanford, California, USA

    Jennifer R Cochran

  11. Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Darrell J Irvine

  12. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA

    Darrell J Irvine

Authors
  1. Kelly D Moynihan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cary F Opel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gregory L Szeto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alice Tzeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eric F Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jesse M Engreitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert T Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kavya Rakhra
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael H Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Adrienne M Rothschilds
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sudha Kumari
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ryan L Kelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Byron H Kwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Wuhbet Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kevin Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Naveen K Mehta
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Monique J Kauke
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Heikyung Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Jennifer R Cochran
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Douglas A Lauffenburger
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. K Dane Wittrup
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Darrell J Irvine
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.D.M., C.F.O., D.J.I. and K.D.W. designed the studies and wrote the manuscript; K.D.M. and C.F.O. carried out experiments; E.F.Z., A.T., B.H.K., M.J.K. and H.S. assisted with protein production; J.M.E. assisted in generating the Trp2-knockout line using CRISPR–Cas9; K.R., A.T., E.F.Z., W.A., R.T.W., A.M.R., R.L.K., N.K.M. and K.H. assisted with experiments; G.L.S. designed and analyzed intratumoral Luminex, and assisted in flow cytometry design and writing of the manuscript; D.A.L. aided with multivariate analysis of intratumoral Luminex data; G.L.S. and M.H.Z. conducted intratumoral Luminex and assisted with Braf/Pten mouse experiments; S.K. assisted with immunofluorescence microscopy; and J.R.C. supplied 2.5F–Fc reagents.

Corresponding authors

Correspondence to K Dane Wittrup or Darrell J Irvine.

Ethics declarations

Competing interests

D.J.I. holds equity in Vedantra Pharmaceuticals, which holds a license to the amphiphile–vaccine technology used in these studies.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9, Supplementary Tables 1 and 2 (PDF 28714 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moynihan, K., Opel, C., Szeto, G. et al. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat Med 22, 1402–1410 (2016). https://doi.org/10.1038/nm.4200

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4200

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing