Limits...
Expansion of melanoma-specific cytolytic CD8+ T cell precursors in patients with metastatic melanoma vaccinated with CD34+ progenitor-derived dendritic cells.

Paczesny S, Banchereau J, Wittkowski KM, Saracino G, Fay J, Palucka AK - J. Exp. Med. (2004)

Bottom Line: Cancer vaccines aim at inducing (a) tumor-specific effector T cells able to reduce/eliminate the tumor mass, and (b) long-lasting tumor-specific memory T cells able to control tumor relapse.Thus, CD34-DC vaccines can expand melanoma-specific CTL precursors that can kill melanoma antigen-expressing targets.These results justify the design of larger follow-up studies to assess the immunological and clinical response to peptide-pulsed CD34-DC vaccines.

View Article: PubMed Central - PubMed

Affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204, USA.

ABSTRACT
Cancer vaccines aim at inducing (a) tumor-specific effector T cells able to reduce/eliminate the tumor mass, and (b) long-lasting tumor-specific memory T cells able to control tumor relapse. We have shown earlier, in 18 human histocompatibility leukocyte antigen (HLA)-A*0201 patients with metastatic melanoma, that vaccination with peptide-loaded CD34-dendritic cells (DCs) leads to expansion of melanoma-specific interferon gamma-producing CD8+ T cells in the blood. Here, we show in 9 out of 12 analyzed patients the expansion of cytolytic CD8+ T cell precursors specific for melanoma differentiation antigens. These precursors yield, upon single restimulation with melanoma peptide-pulsed DCs, cytotoxic T lymphocytes (CTLs) able to kill melanoma cells. Melanoma-specific CTLs can be grown in vitro and can be detected in three assays: (a) melanoma tetramer binding, (b) killing of melanoma peptide-pulsed T2 cells, and (c) killing of HLA-A*0201 melanoma cells. The cytolytic activity of expanded CTLs correlates with the frequency of melanoma tetramer binding CD8+ T cells. Thus, CD34-DC vaccines can expand melanoma-specific CTL precursors that can kill melanoma antigen-expressing targets. These results justify the design of larger follow-up studies to assess the immunological and clinical response to peptide-pulsed CD34-DC vaccines.

Show MeSH

Related in: MedlinePlus

CTL function correlates with the frequency of tetramer-binding CD8+ T cells. (a) The specific lysis, by CD8+ T cells restimulated with melanoma peptide–pulsed DCs, of melanoma peptide–pulsed T2 cells (ordinate), but not of PSA peptide–pulsed T2 cells, correlates with the frequency of all high affinity/intensity melanoma tetramers binding CD8+ T cells determined used u-scores (abscissa). Nonparametric Spearman correlation. (b) The specific lysis of Me275 melanoma cells by CD8+T cells restimulated with melanoma peptide–pulsed DCs (ordinate) correlates with the frequency of all high affinity/intensity melanoma tetramers binding CD8+ T cells determined used u-scores (abscissa). There was no correlation between tetramer scores and the killing of control MCF7 cells. Nonparametric Spearman correlation.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211788&req=5

fig5: CTL function correlates with the frequency of tetramer-binding CD8+ T cells. (a) The specific lysis, by CD8+ T cells restimulated with melanoma peptide–pulsed DCs, of melanoma peptide–pulsed T2 cells (ordinate), but not of PSA peptide–pulsed T2 cells, correlates with the frequency of all high affinity/intensity melanoma tetramers binding CD8+ T cells determined used u-scores (abscissa). Nonparametric Spearman correlation. (b) The specific lysis of Me275 melanoma cells by CD8+T cells restimulated with melanoma peptide–pulsed DCs (ordinate) correlates with the frequency of all high affinity/intensity melanoma tetramers binding CD8+ T cells determined used u-scores (abscissa). There was no correlation between tetramer scores and the killing of control MCF7 cells. Nonparametric Spearman correlation.

Mentions: Lastly, we determined whether the increased killing of cells expressing melanoma antigens (either T2 or melanoma cells) in response to DC vaccination correlates with the increased frequency of melanoma-specific CD8+ T cells, using u-scores for the profiles of the counts of CD8+ T cells binding each of the melanoma tetramers, i.e., gp100, MART-1/Melan A, tyrosinase, and MAGE-3 (Table S3). As shown in Fig. 5 a, the killing of melanoma peptide–pulsed T2 targets was strongly correlated (r = 0.75, P = 0.006) with the overall frequency of melanoma-specific CD8+ T cells. In contrast, there was no correlation between the frequency of melanoma-specific CD8+ T cells and the killing of control PSA peptide–pulsed T2 targets (r = 0.12, P = 0.73; Fig. 5 a). In line with the T2 assay, the killing of Me275 melanoma cells was strongly correlated (r = 0.85, P = 0.0008) with the overall frequency of melanoma-specific CD8+ T cells (Fig. 5 b). The killing of control cell lines MCF7 or K562, did not correlate with the frequency of melanoma-specific CD8+ T cells (P > 0.1), which again indicates specificity.


Expansion of melanoma-specific cytolytic CD8+ T cell precursors in patients with metastatic melanoma vaccinated with CD34+ progenitor-derived dendritic cells.

Paczesny S, Banchereau J, Wittkowski KM, Saracino G, Fay J, Palucka AK - J. Exp. Med. (2004)

CTL function correlates with the frequency of tetramer-binding CD8+ T cells. (a) The specific lysis, by CD8+ T cells restimulated with melanoma peptide–pulsed DCs, of melanoma peptide–pulsed T2 cells (ordinate), but not of PSA peptide–pulsed T2 cells, correlates with the frequency of all high affinity/intensity melanoma tetramers binding CD8+ T cells determined used u-scores (abscissa). Nonparametric Spearman correlation. (b) The specific lysis of Me275 melanoma cells by CD8+T cells restimulated with melanoma peptide–pulsed DCs (ordinate) correlates with the frequency of all high affinity/intensity melanoma tetramers binding CD8+ T cells determined used u-scores (abscissa). There was no correlation between tetramer scores and the killing of control MCF7 cells. Nonparametric Spearman correlation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211788&req=5

fig5: CTL function correlates with the frequency of tetramer-binding CD8+ T cells. (a) The specific lysis, by CD8+ T cells restimulated with melanoma peptide–pulsed DCs, of melanoma peptide–pulsed T2 cells (ordinate), but not of PSA peptide–pulsed T2 cells, correlates with the frequency of all high affinity/intensity melanoma tetramers binding CD8+ T cells determined used u-scores (abscissa). Nonparametric Spearman correlation. (b) The specific lysis of Me275 melanoma cells by CD8+T cells restimulated with melanoma peptide–pulsed DCs (ordinate) correlates with the frequency of all high affinity/intensity melanoma tetramers binding CD8+ T cells determined used u-scores (abscissa). There was no correlation between tetramer scores and the killing of control MCF7 cells. Nonparametric Spearman correlation.
Mentions: Lastly, we determined whether the increased killing of cells expressing melanoma antigens (either T2 or melanoma cells) in response to DC vaccination correlates with the increased frequency of melanoma-specific CD8+ T cells, using u-scores for the profiles of the counts of CD8+ T cells binding each of the melanoma tetramers, i.e., gp100, MART-1/Melan A, tyrosinase, and MAGE-3 (Table S3). As shown in Fig. 5 a, the killing of melanoma peptide–pulsed T2 targets was strongly correlated (r = 0.75, P = 0.006) with the overall frequency of melanoma-specific CD8+ T cells. In contrast, there was no correlation between the frequency of melanoma-specific CD8+ T cells and the killing of control PSA peptide–pulsed T2 targets (r = 0.12, P = 0.73; Fig. 5 a). In line with the T2 assay, the killing of Me275 melanoma cells was strongly correlated (r = 0.85, P = 0.0008) with the overall frequency of melanoma-specific CD8+ T cells (Fig. 5 b). The killing of control cell lines MCF7 or K562, did not correlate with the frequency of melanoma-specific CD8+ T cells (P > 0.1), which again indicates specificity.

Bottom Line: Cancer vaccines aim at inducing (a) tumor-specific effector T cells able to reduce/eliminate the tumor mass, and (b) long-lasting tumor-specific memory T cells able to control tumor relapse.Thus, CD34-DC vaccines can expand melanoma-specific CTL precursors that can kill melanoma antigen-expressing targets.These results justify the design of larger follow-up studies to assess the immunological and clinical response to peptide-pulsed CD34-DC vaccines.

View Article: PubMed Central - PubMed

Affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204, USA.

ABSTRACT
Cancer vaccines aim at inducing (a) tumor-specific effector T cells able to reduce/eliminate the tumor mass, and (b) long-lasting tumor-specific memory T cells able to control tumor relapse. We have shown earlier, in 18 human histocompatibility leukocyte antigen (HLA)-A*0201 patients with metastatic melanoma, that vaccination with peptide-loaded CD34-dendritic cells (DCs) leads to expansion of melanoma-specific interferon gamma-producing CD8+ T cells in the blood. Here, we show in 9 out of 12 analyzed patients the expansion of cytolytic CD8+ T cell precursors specific for melanoma differentiation antigens. These precursors yield, upon single restimulation with melanoma peptide-pulsed DCs, cytotoxic T lymphocytes (CTLs) able to kill melanoma cells. Melanoma-specific CTLs can be grown in vitro and can be detected in three assays: (a) melanoma tetramer binding, (b) killing of melanoma peptide-pulsed T2 cells, and (c) killing of HLA-A*0201 melanoma cells. The cytolytic activity of expanded CTLs correlates with the frequency of melanoma tetramer binding CD8+ T cells. Thus, CD34-DC vaccines can expand melanoma-specific CTL precursors that can kill melanoma antigen-expressing targets. These results justify the design of larger follow-up studies to assess the immunological and clinical response to peptide-pulsed CD34-DC vaccines.

Show MeSH
Related in: MedlinePlus