Intratumoral electroporation of IL-12 cDNA eradicates established melanomas by Trp2180-188-specific CD8+ CTLs in a perforin/granzyme-mediated and IFN-c-dependent manner: Application of Trp2180-188 peptides

Jeong Im Sin, Jae Bok Park, In Hee Lee, Daehan Park, Youn Seok Choi, Jongseon Choe, Esteban Celis

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Intratumoral electroporation (IT-EP) with IL-12 cDNA (IT-EP/IL12) can lead to the eradication of established B16 melanoma tumors in mice. Here, we explore the immunological mechanism of the antitumor effects generated by this therapy. The results show that ITEP/ IL12 applied only once resulted in eradication in 70% animals with large established B16 tumors. Tumor eradication required the participation of CD8+ T cells, but not CD4+ T cells and NK cells. IT-EP/IL12 induced antigenspecific CD8+ T cell responses against the immunodominant Trp2180-188 epitope and generated a systemic response, resulting in significant therapeutic effects against distal, untreated tumors. The therapeutic effect of IT-EP/ IL12 was absent in perforin-deficient mice, indicating that tumor elimination occurred through conventional perforin/ granzyme lysis by CTLs. Moreover, this therapy induced some degree of immunological memory that protected approximately one-third of the cured mice against a subsequent tumor challenge. Moreover, antitumor efficacy and long-term protection against B16 were significantly improved by concurrent Trp2 peptide immunization through more induction of Ag-specific CTL responses and more attraction of IFN-c-expressing CD8+ T cells into tumor sites. The antitumor effect of IT-EP/IL12 required the participation of IFN-c, which was shown to induce MHC class I expression on B16 cells and increase the lytic activity of the CD8+ CTL generated by IT-EP/IL12. The results from these animal studies may help in the development of IT-EP/IL12 for cancer patients.

Original languageEnglish (US)
Pages (from-to)1671-1682
Number of pages12
JournalCancer Immunology, Immunotherapy
Volume61
Issue number10
DOIs
StatePublished - Oct 1 2012
Externally publishedYes

Fingerprint

Granzymes
Perforin
Electroporation
Interleukin-12
Melanoma
Complementary DNA
Peptides
Neoplasms
T-Lymphocytes
Therapeutic Uses
Immunologic Memory
Experimental Melanomas
Natural Killer Cells
Epitopes
Immunization
Therapeutics

Keywords

  • Antitumor immunity
  • Electroporation
  • IL-12
  • Melanoma

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

Cite this

Intratumoral electroporation of IL-12 cDNA eradicates established melanomas by Trp2180-188-specific CD8+ CTLs in a perforin/granzyme-mediated and IFN-c-dependent manner : Application of Trp2180-188 peptides. / Sin, Jeong Im; Park, Jae Bok; Lee, In Hee; Park, Daehan; Choi, Youn Seok; Choe, Jongseon; Celis, Esteban.

In: Cancer Immunology, Immunotherapy, Vol. 61, No. 10, 01.10.2012, p. 1671-1682.

Research output: Contribution to journalArticle

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abstract = "Intratumoral electroporation (IT-EP) with IL-12 cDNA (IT-EP/IL12) can lead to the eradication of established B16 melanoma tumors in mice. Here, we explore the immunological mechanism of the antitumor effects generated by this therapy. The results show that ITEP/ IL12 applied only once resulted in eradication in 70{\%} animals with large established B16 tumors. Tumor eradication required the participation of CD8+ T cells, but not CD4+ T cells and NK cells. IT-EP/IL12 induced antigenspecific CD8+ T cell responses against the immunodominant Trp2180-188 epitope and generated a systemic response, resulting in significant therapeutic effects against distal, untreated tumors. The therapeutic effect of IT-EP/ IL12 was absent in perforin-deficient mice, indicating that tumor elimination occurred through conventional perforin/ granzyme lysis by CTLs. Moreover, this therapy induced some degree of immunological memory that protected approximately one-third of the cured mice against a subsequent tumor challenge. Moreover, antitumor efficacy and long-term protection against B16 were significantly improved by concurrent Trp2 peptide immunization through more induction of Ag-specific CTL responses and more attraction of IFN-c-expressing CD8+ T cells into tumor sites. The antitumor effect of IT-EP/IL12 required the participation of IFN-c, which was shown to induce MHC class I expression on B16 cells and increase the lytic activity of the CD8+ CTL generated by IT-EP/IL12. The results from these animal studies may help in the development of IT-EP/IL12 for cancer patients.",
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