Restoration of tumor-specific HLA class I restricted cytotoxicity in tumor infiltrating lymphocytes of advanced breast cancer patients by in vitro stimulation with tumor antigen-pulsed autologous dendritic cells

Rena Kass, Stefania Bellone, Michela Palmieri, Stefania Canè, Eliana Bignotti, Rhonda Henry-Tillman, Laura Hutchins, Martin J. Cannon, Vicki Klimberg, Alessandro D. Santin

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Breast tumor infiltrating lymphocytes (TIL) are enriched in tumor-specific cytotoxic T lymphocytes (CTL), and may represent a superior source of CTL compare to peripheral blood lymphocytes (PBL), for adoptive T cell immunotherapy of breast cancer. However, the immunocompetence of TIL and the possibility to consistently restore their tumor-specific lytic activity in vitro remains an open issue. In this study we evaluated the potential of tumor antigen-pulsed fully mature dendritic cell (DC) stimulation in restoring tumor-specific cytotoxicity in anergic TIL populations from advanced breast cancer patients. In addition we have compared tumor-specific T cell responses induced by tumor antigen-loaded DC stimulation of TIL to responses induced from PBL. Although TIL were consistently non-cytotoxic after isolation or culture in the presence of interleukin-2 (IL-2), in matched experiments from three consecutive patients, tumor-lysate-pulsed DC-stimulated CD8+ T cell derived from TIL were found to be significantly more cytotoxic than PBL (p < 0.05). In addition, cytotoxicity against autologous tumor cells was more significantly inhibited by an anti-HLA class I (W6/32) MAb in TIL compared to PBL (p < 0.05). CTL populations derived from TIL and PBL did not lyse autologous EBV-transformed lymphoblastoid cell lines, and showed negligible cytotoxicity against the NK-sensitive cell line K562. Furthermore, in both CD8+ T cell populations the majority of the tumor-specific CTL exhibited a Th1 cytokine bias (IFN-γhigh/IL-4low). Taken together, these data show that tumor lysate-pulsed mature DC can consistently restore tumor-specific lytic activity in non-cytotoxic breast cancer TIL. These results may have important implications for the treatment of chemotherapy resistant breast cancer with active or adoptive immunotherapy.

Original languageEnglish (US)
Pages (from-to)275-285
Number of pages11
JournalBreast Cancer Research and Treatment
Volume80
Issue number3
DOIs
StatePublished - Aug 2003
Externally publishedYes

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Tumor-Infiltrating Lymphocytes
Neoplasm Antigens
Dendritic Cells
Breast Neoplasms
Cytotoxic T-Lymphocytes
Neoplasms
Lymphocytes
T-Lymphocytes
Population
Adoptive Immunotherapy
In Vitro Techniques
Immunocompetence
Active Immunotherapy
Transformed Cell Line
Human Herpesvirus 4
Natural Killer Cells
Immunotherapy
Interleukin-2
Cytokines
Drug Therapy

Keywords

  • Breast cancer
  • CTLs
  • Dendritic cells
  • TIL
  • Tumor lysate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Restoration of tumor-specific HLA class I restricted cytotoxicity in tumor infiltrating lymphocytes of advanced breast cancer patients by in vitro stimulation with tumor antigen-pulsed autologous dendritic cells. / Kass, Rena; Bellone, Stefania; Palmieri, Michela; Canè, Stefania; Bignotti, Eliana; Henry-Tillman, Rhonda; Hutchins, Laura; Cannon, Martin J.; Klimberg, Vicki; Santin, Alessandro D.

In: Breast Cancer Research and Treatment, Vol. 80, No. 3, 08.2003, p. 275-285.

Research output: Contribution to journalArticle

Kass, Rena ; Bellone, Stefania ; Palmieri, Michela ; Canè, Stefania ; Bignotti, Eliana ; Henry-Tillman, Rhonda ; Hutchins, Laura ; Cannon, Martin J. ; Klimberg, Vicki ; Santin, Alessandro D. / Restoration of tumor-specific HLA class I restricted cytotoxicity in tumor infiltrating lymphocytes of advanced breast cancer patients by in vitro stimulation with tumor antigen-pulsed autologous dendritic cells. In: Breast Cancer Research and Treatment. 2003 ; Vol. 80, No. 3. pp. 275-285.
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abstract = "Breast tumor infiltrating lymphocytes (TIL) are enriched in tumor-specific cytotoxic T lymphocytes (CTL), and may represent a superior source of CTL compare to peripheral blood lymphocytes (PBL), for adoptive T cell immunotherapy of breast cancer. However, the immunocompetence of TIL and the possibility to consistently restore their tumor-specific lytic activity in vitro remains an open issue. In this study we evaluated the potential of tumor antigen-pulsed fully mature dendritic cell (DC) stimulation in restoring tumor-specific cytotoxicity in anergic TIL populations from advanced breast cancer patients. In addition we have compared tumor-specific T cell responses induced by tumor antigen-loaded DC stimulation of TIL to responses induced from PBL. Although TIL were consistently non-cytotoxic after isolation or culture in the presence of interleukin-2 (IL-2), in matched experiments from three consecutive patients, tumor-lysate-pulsed DC-stimulated CD8+ T cell derived from TIL were found to be significantly more cytotoxic than PBL (p < 0.05). In addition, cytotoxicity against autologous tumor cells was more significantly inhibited by an anti-HLA class I (W6/32) MAb in TIL compared to PBL (p < 0.05). CTL populations derived from TIL and PBL did not lyse autologous EBV-transformed lymphoblastoid cell lines, and showed negligible cytotoxicity against the NK-sensitive cell line K562. Furthermore, in both CD8+ T cell populations the majority of the tumor-specific CTL exhibited a Th1 cytokine bias (IFN-γhigh/IL-4low). Taken together, these data show that tumor lysate-pulsed mature DC can consistently restore tumor-specific lytic activity in non-cytotoxic breast cancer TIL. These results may have important implications for the treatment of chemotherapy resistant breast cancer with active or adoptive immunotherapy.",
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AU - Bignotti, Eliana

AU - Henry-Tillman, Rhonda

AU - Hutchins, Laura

AU - Cannon, Martin J.

AU - Klimberg, Vicki

AU - Santin, Alessandro D.

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