Skip to main content

Advertisement

SpringerLink
Log in

Combination of mAb-AR20.5, anti-PD-L1 and PolyICLC inhibits tumor progression and prolongs survival of MUC1.Tg mice challenged with pancreatic tumors

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

A substantial body of evidence suggests the existence of MUC1-specific antibodies and cytotoxic T cell activities in pancreatic cancer patients. However, tumor-induced immunosuppression renders these responses ineffective. The current study explores a novel therapeutic combination wherein tumor-bearing hosts can be immunologically primed with their own antigen, through opsonization with a tumor antigen-targeted antibody, mAb-AR20.5. We evaluated the efficacy of immunization with this antibody in combination with PolyICLC and anti-PD-L1. The therapeutic combination of mAb-AR20.5 + anti-PD-L1 + PolyICLC induced rejection of human MUC1 expressing tumors and provided a long-lasting, MUC1-specific cellular immune response, which could be adoptively transferred and shown to provide protection against tumor challenge in human MUC1 transgenic (MUC.Tg) mice. Furthermore, antibody depletion studies revealed that CD8 cells were effectors for the MUC1-specific immune response generated by the mAb-AR20.5 + anti-PD-L1 + PolyICLC combination. Multichromatic flow cytometry data analysis demonstrated a significant increase over time in circulating, activated CD8 T cells, CD3+CD4−CD8−(DN) T cells, and mature dendritic cells in mAb-AR20.5 + anti-PD-L1 + PolyICLC combination-treated, tumor-bearing mice, as compared to saline-treated control counterparts. Our study provides a proof of principle that an effective and long-lasting anti-tumor cellular immunity can be achieved in pancreatic tumor-bearing hosts against their own antigen (MUC1), which can be further potentiated using a vaccine adjuvant and an immune checkpoint inhibitor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

ADCC:

Antibody-dependent cell-mediated cytotoxicity

ANOVA:

Analysis of variance

BSA:

Bovine serum albumin

CFSE:

Carboxyfluorescein succinimidyl ester

DN T cells:

Double negative T cells

ELISA:

Enzyme-linked immunosorbent assay

FACS:

Fluorescence-activated cell sorting

gp:

Group

γδT cells:

Gamma delta T cells

GVAX:

Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transfected tumor cell vaccine

HLA-DR:

Human leukocyte antigen–antigen D related

IACUC:

Institutional Animal Care and Use Committee

IFN-γ:

Interferon gamma

i.p :

Intraperitoneal injection

iNKT cells:

Invariant natural killer T cells

KPC:

LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre

KPC.MUC1:

KPC tumors expressing human MUC1

LAG-3:

Lymphocyte activation gene 3

MFI:

Mean fluorescence intensity

MHC:

Major histocompatibility complex

MsIgG1:

Mouse IgG1

MUC1:

Mucin 1

MUC1.Tg:

Human MUC1 transgenic

NK cells:

Natural killer cells

PDAC:

Pancreatic ductal adenocarcinoma

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed death-Ligand 1

PMA:

Phorbol 12-myristate 13-acetate

PolyICLC:

Polyinosinic-polycytidylic acid

TCR:

T-cell receptor

TILs:

Tumor-infiltrating lymphocytes

TLR3:

Toll-like receptor 3

TTP:

Time-to-tumor progression

Type 1 IFN:

Type 1 interferon

References

  1. Kotera Y, Fontenot JD, Pecher G, Metzgar RS, Finn OJ (1994) Humoral immunity against a tandem repeat epitope of human mucin MUC-1 in sera from breast, pancreatic, and colon cancer patients. Cancer Res 54:2856–2860

    CAS  PubMed  Google Scholar 

  2. Barnd DL, Lan MS, Metzgar RS, Finn OJ (1989) Specific, major histocompatibility complex-unrestricted recognition of tumor-associated mucins by human cytotoxic T cells. PNAS 86:7159–7163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Heller A, Zornig I, Muller T et al (2010) Immunogenicity of SEREX-identified antigens and disease outcome in pancreatic cancer. Cancer Immunol Immunother 59:1389–1400

    Article  CAS  PubMed  Google Scholar 

  4. Le DT, Wang-Gillman A, Picozzi V, Greten TF et al (2015) Saftey and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol 33:1325–1333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Beatty GL, Chiorean EG, Fishman MP et al (2011) CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331:1612–1616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Brahmer JR, Tykodi SS, Chow LQ et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Royal RE, Levy C, Turner K et al (2010) Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 33:828–833

    Article  CAS  PubMed  Google Scholar 

  8. de Bono JS, Rha SY, Stephenson J et al (2004) Phase I trial of a murine antibody to MUC1 in patients with metastatic cancer: evidence for the activation of humoral and cellular antitumor immunity. Ann Oncol 15:1825–1833

    Article  PubMed  Google Scholar 

  9. Rowse GJ, Tempero RM, VanLith ML, Hollingsworth MA, Gendler SJ (1998) Tolerance and immunity to MUC1 in a human MUC1 transgenic murine model. Cancer Res 58:315–321

    CAS  PubMed  Google Scholar 

  10. Morikane K, Tempero R, Sivinski CL, Kitajima S, Gendler SJ, Hollingsworth MA (2001) Influence of organ site and tumor cell type on MUC1-specific tumor immunity. Int Immunol 13:233–40

    Article  CAS  PubMed  Google Scholar 

  11. Tempero RM, VanLith ML, Morikane K, Rowse GJ, Gendler SJ, Hollingsworth MA (1998) CD4+ lymphocytes provide MUC1-specific tumor immunity in vivo that is undetectable in vitro and is absent in MUC1 transgenic mice. J Immunol 161:5500–5506

    CAS  PubMed  Google Scholar 

  12. Qi W, Schultes BC, Liu D, Kuzma M, Decker W, Madiyalakan R (2001). Characterization of an anti-MUC1 monoclonal antibody with potential as a cancer vaccine. Hybrid Hybridomics 20:313–324

    Article  CAS  PubMed  Google Scholar 

  13. Bunt SK, Mohr AM, Bailey JM, Grandgenett PM, Hollingsworth MA (2013) Rosiglitazone and gemcitabine in combination reduces immune suppression and modulates T cell populations in pancreatic cancer. Cancer Immunol Immunother 62:225–236

    Article  CAS  PubMed  Google Scholar 

  14. Riches JC, Davies JK, McClanahan F et al (2013) T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 121:1612–1621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Karagiannis SN, Wang Q, East N et al (2003) Activity of human monocytes in IgE antibody-dependent surveillance and killing of ovarian tumor cells. Eur J Immunol 33:1030–1040

    Article  CAS  PubMed  Google Scholar 

  16. Chen L, Han X (2015) Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest 125:3384–3391

    Article  PubMed  PubMed Central  Google Scholar 

  17. Pauken KE, Wherry EJ (2015) Overcoming T cell exhaustion in infection and cancer. Trends Immunol 36:265–276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Duraiswamy J, Freeman GJ, Coukos G (2013) Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res 73:6900–6912

    Article  CAS  PubMed  Google Scholar 

  19. Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G (2015) Type I interferons in anticancer immunity. Nat Rev Immunol 15:405–414

    Article  CAS  PubMed  Google Scholar 

  20. Ibrahim NK, Yariz KO, Bondarenko I et al (2011) Randomized phase II trial of letrozole plus anti-MUC1 antibody AS1402 in hormone receptor-positive locally advanced or metastatic breast cancer. Clin Cancer Res 17:6822–6830

    Article  CAS  PubMed  Google Scholar 

  21. Roulois D, Gregoire M, Fonteneau JF (2013) MUC1-specific cytotoxic T lymphocytes in cancer therapy: induction and challenge. Biomed Res Int. https://doi.org/10.1155/2013/871936

    PubMed  Google Scholar 

  22. Schultes B, Hou F, Smith L, Nicodemus C (2007) Immunization with MUC1-anti-MUC1 immune complexes induces CD4 and CD8 T cell responses and provides tumor control in MUC1-tg mice. In: AACR annual meeting proceedings. Cancer Res 67 (Abstr 5097)

  23. Schultes BC, Eng H, Agopsowicz K, Nicodemus CF (2004) Potent helper and cytolytic T cell response by dendritic cells armed with MUC1-anti-MUC1 immune complexes. In: 12th International congress of immunology and 4th annual conference of FOCIS, CIM, 27(4) (Abstr 53.102)

  24. Schultes BC, Kuzma ML, Agopsowicz K et al (2002) Antibodies as vaccines immune complexes allow for efficient uptake and processing of antigens on MHC class I and II and induce maturation of dendritic cells. Experimental biology (AAI meeting). FASEB J 16:A334 (Abstr 246.12).

    Google Scholar 

  25. Mukherjee P, Basu GD, Tinder TL et al (2009) Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition. J Immunol 182:216–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mortenson ED, Park S, Jiang Z, Wang S, Fu YX (2013) Effective anti-neu-initiated antitumor responses require the complex role of CD4+ T cells. Clin Cancer Res 19:1476–1486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tumeh PC, Harview CL, Yearley JH et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Soares KC, Rucki AA, Wu AA et al (2015) PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J Immunother 38:1–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Postow MA, Callahan MK, Wolchok JD (2015) Immune checkpoint blockade in cancer therapy. J Clin Oncol 33:1974–1982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gajewski TF, Corrales L (2015) New perspectives on type I IFNs in cancer. Cytokine Growth Factor Rev 26:175–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nagato T, Lee YR, Harabuchi Y, Celis E (2014) Combinatorial immunotherapy of polyinosinic-polycytidylic acid and blockade of programmed death-ligand 1 induce effective CD8 T-cell responses against established tumors. Clin Cancer Res 20:1223–1234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kohlgraf KG, Gawron AJ, Higashi M et al (2004) Tumor-specific immunity in MUC1.Tg mice induced by immunization with peptide vaccines from the cytoplasmic tail of CD227 (MUC1). Cancer Immunol Immunother 53:1068–1084

    Article  CAS  PubMed  Google Scholar 

  35. D’Acquisto F, Crompton T (2011) CD3+ CD4−CD8−(double negative) T cells: saviours or villains of the immune response? Biochem Pharmacol 82:333–340

    Article  PubMed  Google Scholar 

  36. Young KJ, Kay LS, Phillips MJ, Zhang L (2003) Antitumor activity mediated by double-negative T cells. Cancer Res 63:8014–8021

    CAS  PubMed  Google Scholar 

  37. Gomes AQ, Martins DS, Silva-Santos B (2010) Targeting gamma delta T lymphocytes for cancer immunotherapy: from novel mechanistic insight to clinical application. Cancer Res 70:10024–10027

    Article  CAS  PubMed  Google Scholar 

  38. Seidel UJ, Vogt F, Grosse-Hovest L, Jung G, Handgretinger R, Lang P (2014) gamma delta T cell-mediated antibody-dependent cellular cytotoxicity with CD19 antibodies assessed by an impedance-based label-free real-time cytotoxicity assay. Front Immunol 5:618

    Article  PubMed  PubMed Central  Google Scholar 

  39. Hossain MS, Takimoto H, Ninomiya T et al (2000) Characterization of CD4– CD8– CD3+ T-cell receptor-alpha beta + T cells in murine cytomegalovirus infection. Immunology 101:19–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. van der Vliet HJ, Molling JW, Nishi N et al (2003) Polarization of Valpha24+ Vbeta11+ natural killer T cells of healthy volunteers and cancer patients using alpha-galactosylceramide-loaded and environmentally instructed dendritic cells. Cancer Res 63:4101–4106

    PubMed  Google Scholar 

  41. Deniger DC, Moyes JS, Cooper LJ (2014) Clinical applications of gamma delta T cells with multivalent immunity. Front Immunol 5:636

    Article  PubMed  PubMed Central  Google Scholar 

  42. Gao Y, Yang W, Pan M et al (2003) Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J Exp Med 198:433–442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wesch D, Beetz S, Oberg HH, Marget M, Krengel K, Kabelitz D (2006) Direct costimulatory effect of TLR3 ligand poly(I:C) on human gamma delta T lymphocytes. J Immunol 176:1348–1354

    Article  CAS  PubMed  Google Scholar 

  44. Pylayeva-Gupta Y, Das S, Handler JS et al (2016) IL35-producing b cells promote the development of pancreatic neoplasia. Cancer Discov 6:247–255

    Article  CAS  PubMed  Google Scholar 

  45. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339:1546–1558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE, 68198-6805, USA

    Kamiya Mehla, James A. Grunkemeyer, Kelly A. O’Connell, Maria M. Steele, Thomas C. Caffrey, Pankaj K. Singh & Michael A. Hollingsworth

  2. Mercaptor Discoveries Inc, Novato, CA, USA

    Jarrod Tremayne

  3. Shanghai Jiao Tong University School of Medicine, Lu Wan Qu, Shanghai Shi, China

    Xinyi Zhu

  4. Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA

    Fang Yu

  5. Unum Therapeutics, Boston, MA, USA

    Birgit C. Schultes

  6. OncoQuest Inc., Edmonton, AB, Canada

    Ragupathy Madiyalakan

  7. AIT Strategies, Franconia, NH, USA

    Christopher F. Nicodemus

Authors
  1. Kamiya Mehla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jarrod Tremayne
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James A. Grunkemeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kelly A. O’Connell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria M. Steele
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas C. Caffrey
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xinyi Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pankaj K. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Birgit C. Schultes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ragupathy Madiyalakan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christopher F. Nicodemus
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michael A. Hollingsworth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael A. Hollingsworth.

Ethics declarations

Conflict of interest

The authors have no conflict of interest.

Funding

This study was supported by the grants from the National Cancer Institute (CA127297, CA163120, CA036727, and CA163649). Kamiya Mehla is supported by Project Purple Jayne Snyder Pancreatic Cancer Research Fellowship Grant.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 8710 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mehla, K., Tremayne, J., Grunkemeyer, J.A. et al. Combination of mAb-AR20.5, anti-PD-L1 and PolyICLC inhibits tumor progression and prolongs survival of MUC1.Tg mice challenged with pancreatic tumors. Cancer Immunol Immunother 67, 445–457 (2018). https://doi.org/10.1007/s00262-017-2095-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-017-2095-7

Keywords

Search

Navigation