Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity

Jorge Schettini, Amritha Kidiyoor, Dahlia M. Besmer, Teresa L. Tinder, Lopamudra Das Roy, Joseph Lustgarten, Sandra J Gendler, Pinku Mukherjee

Research output: Contribution to journalArticle

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Abstract

Monoclonal antibodies (mAbs) against tumorassociated antigens are useful anticancer agents. Antibodydependent cellular cytotoxicity (ADCC) is one of the major mechanisms responsible for initiating natural killer cell (NK)-mediated killing of tumors. However, the regulation of ADCC via NK cells is poorly understood. We have investigated the cytolytic activity of NK cells against pancreatic cancer cells that were coated with an antibody directed against the human tumor antigen, Mucin-1 designated HMFG-2, either alone or conjugated to CpG oligodeoxynucleotide (CpG ODN). Conjugated antibodies were tested for their ability to elicit ADCC in vitro and in vivo against pancreatic cancer cells. NK cells cultured in the presence of immobilized CpG ODN, HMFG-2 Ab, or CpG ODN-conjugated HMFG-2 Ab were able to up-regulate perforin similarly. Interestingly, a significant higher ADCC was observed when CpG ODN-conjugated HMFG- 2-coated tumor cells were co-cultured with NK cells compared to unconjugated HMFG-2 Ab or CpG ODN alone. Moreover, MyD88-deficient NK cells can perform ADCC in vitro. Furthermore, intratumoral injections of CpG ODN-conjugated HMFG-2 induced a significant reduction in tumor burden in vivo in an established model of pancreatic tumor in nude mice compared to CpG ODN or the HMFG-2 alone. Depletion of macrophages or NK cells before treatment confirmed that both cells were required for the anti-tumor response in vivo. Results also suggest that CpG ODN and HMFG-2 Ab could be sensed by NK cells on the mAb-coated tumor cells triggering enhanced ADCC in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)2055-2065
Number of pages11
JournalCancer Immunology, Immunotherapy
Volume61
Issue number11
DOIs
StatePublished - Nov 2012

Fingerprint

Natural Killer Cells
Anti-Idiotypic Antibodies
Oligodeoxyribonucleotides
Neoplasms
Pancreatic Neoplasms
Mucin-1
Perforin
Antibodies
Neoplasm Antigens
Tumor Burden
Nude Mice
Antineoplastic Agents
Cultured Cells
Up-Regulation
Macrophages
Monoclonal Antibodies
Antigens
Injections

Keywords

  • Cancer vaccines
  • Immune response to cancer
  • Immunoconjugates
  • Immunotherapy
  • Pancreatic cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy

Cite this

Schettini, J., Kidiyoor, A., Besmer, D. M., Tinder, T. L., Roy, L. D., Lustgarten, J., ... Mukherjee, P. (2012). Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity. Cancer Immunology, Immunotherapy, 61(11), 2055-2065. https://doi.org/10.1007/s00262-012-1264-y

Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity. / Schettini, Jorge; Kidiyoor, Amritha; Besmer, Dahlia M.; Tinder, Teresa L.; Roy, Lopamudra Das; Lustgarten, Joseph; Gendler, Sandra J; Mukherjee, Pinku.

In: Cancer Immunology, Immunotherapy, Vol. 61, No. 11, 11.2012, p. 2055-2065.

Research output: Contribution to journalArticle

Schettini, J, Kidiyoor, A, Besmer, DM, Tinder, TL, Roy, LD, Lustgarten, J, Gendler, SJ & Mukherjee, P 2012, 'Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity', Cancer Immunology, Immunotherapy, vol. 61, no. 11, pp. 2055-2065. https://doi.org/10.1007/s00262-012-1264-y
Schettini, Jorge ; Kidiyoor, Amritha ; Besmer, Dahlia M. ; Tinder, Teresa L. ; Roy, Lopamudra Das ; Lustgarten, Joseph ; Gendler, Sandra J ; Mukherjee, Pinku. / Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity. In: Cancer Immunology, Immunotherapy. 2012 ; Vol. 61, No. 11. pp. 2055-2065.
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abstract = "Monoclonal antibodies (mAbs) against tumorassociated antigens are useful anticancer agents. Antibodydependent cellular cytotoxicity (ADCC) is one of the major mechanisms responsible for initiating natural killer cell (NK)-mediated killing of tumors. However, the regulation of ADCC via NK cells is poorly understood. We have investigated the cytolytic activity of NK cells against pancreatic cancer cells that were coated with an antibody directed against the human tumor antigen, Mucin-1 designated HMFG-2, either alone or conjugated to CpG oligodeoxynucleotide (CpG ODN). Conjugated antibodies were tested for their ability to elicit ADCC in vitro and in vivo against pancreatic cancer cells. NK cells cultured in the presence of immobilized CpG ODN, HMFG-2 Ab, or CpG ODN-conjugated HMFG-2 Ab were able to up-regulate perforin similarly. Interestingly, a significant higher ADCC was observed when CpG ODN-conjugated HMFG- 2-coated tumor cells were co-cultured with NK cells compared to unconjugated HMFG-2 Ab or CpG ODN alone. Moreover, MyD88-deficient NK cells can perform ADCC in vitro. Furthermore, intratumoral injections of CpG ODN-conjugated HMFG-2 induced a significant reduction in tumor burden in vivo in an established model of pancreatic tumor in nude mice compared to CpG ODN or the HMFG-2 alone. Depletion of macrophages or NK cells before treatment confirmed that both cells were required for the anti-tumor response in vivo. Results also suggest that CpG ODN and HMFG-2 Ab could be sensed by NK cells on the mAb-coated tumor cells triggering enhanced ADCC in vitro and in vivo.",
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