An expanded peripheral T cell population to a cytotoxic T lymphocyte (CTL)-defined, melanocyte-specific antigen in metastatic melanoma patients impacts on generation of peptide-specific CTLs but does not overcome tumor escape from immune surveillance in metastatic lesions

Andrea Anichini, Alessandra Molla, Roberta Mortarini, Gabrina Tragni, Ilaria Bersani, Massimo Di Nicola, Alessandro M. Gianni, Silvana Pilotti, Rod Dunbar, Vincenzo Cerundolo, Giorgio Parmiani

Research output: Contribution to journalArticle

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Abstract

It is not known if immune response to T cell-defined human histocompatibility leukocyte antigen (HLA) class I-restricted melanoma antigens leads to an expanded peripheral pool of T cells in all patients, affects cytotoxic T lymphocyte (CTL) generation, and correlates with antitumor response in metastatic lesions. To this end, a limiting dilution analysis technique was developed that allowed us to evaluate the same frequency of peptide-specific T cells as by staining T cells with HLA-peptide tetrameric complexes. In four out of nine patients, Melan-A/Mart-127-35- specific CTL precursors (CTLp) were ≥1/2,000 peripheral blood lymphocytes and found mostly or only in the CD45RO+ memory T cell subset. In the remaining five patients, a low (+ naive T cell subset. Evaluation of CTL effector frequency after bulk culture indicated that peptide-specific CTLs could be activated in all patients by using professional antigen-presenting cells as dendritic cells, but CTLp frequency determined the kinetics of generation of specificity and the final number of effectors as evaluated by both limiting dilution analysis and staining with HLA-A*0201-Melan-A/Mart-1 tetrameric complexes. Immunohistochemical analysis of 26 neoplastic lesions from the nine patients indicated absence of tumor regression in most instances, even in patients with an expanded peripheral T cell pool to Melan-A/Mart-1 and whose neoplastic lesions contained a high frequency of tetramer-positive Melan-A/Mart-1-specific T cells. Furthermore, frequent lack of a 'brisk' or 'nonbrisk' CD3+CD8+ T cell infiltrate or reduced/absent Melan-A/Mart-1 expression in several lesions and lack of HLA class I antigens were found in some instances. Thus, expansion of peripheral immune repertoire to Melan-A/Mart-1 takes place in some metastatic patients and leads to enhanced CTL induction after antigen-presenting cell-mediated selection, but, in most metastatic lesions, it does not overcome tumor escape from immune surveillance.

Original languageEnglish
Pages (from-to)651-667
Number of pages17
JournalJournal of Experimental Medicine
Volume190
Issue number5
DOIs
Publication statusPublished - Sep 6 1999

Fingerprint

Tumor Escape
MART-1 Antigen
Melanocytes
Cytotoxic T-Lymphocytes
Melanoma
T-Lymphocytes
Antigens
Peptides
HLA Antigens
Histocompatibility Antigens Class I
Population
Histocompatibility Antigens
T-Lymphocyte Subsets
Antigen-Presenting Cells
Staining and Labeling
Melanoma-Specific Antigens
Peptide T
Indicator Dilution Techniques
Dendritic Cells
Lymphocytes

Keywords

  • Cytotoxic T lymphocytes
  • Melan-A/Mart-1
  • Melanoma
  • Peptide-specific CTL precursors
  • Tumor escape

ASJC Scopus subject areas

  • Immunology

Cite this

An expanded peripheral T cell population to a cytotoxic T lymphocyte (CTL)-defined, melanocyte-specific antigen in metastatic melanoma patients impacts on generation of peptide-specific CTLs but does not overcome tumor escape from immune surveillance in metastatic lesions. / Anichini, Andrea; Molla, Alessandra; Mortarini, Roberta; Tragni, Gabrina; Bersani, Ilaria; Di Nicola, Massimo; Gianni, Alessandro M.; Pilotti, Silvana; Dunbar, Rod; Cerundolo, Vincenzo; Parmiani, Giorgio.

In: Journal of Experimental Medicine, Vol. 190, No. 5, 06.09.1999, p. 651-667.

Research output: Contribution to journalArticle

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abstract = "It is not known if immune response to T cell-defined human histocompatibility leukocyte antigen (HLA) class I-restricted melanoma antigens leads to an expanded peripheral pool of T cells in all patients, affects cytotoxic T lymphocyte (CTL) generation, and correlates with antitumor response in metastatic lesions. To this end, a limiting dilution analysis technique was developed that allowed us to evaluate the same frequency of peptide-specific T cells as by staining T cells with HLA-peptide tetrameric complexes. In four out of nine patients, Melan-A/Mart-127-35- specific CTL precursors (CTLp) were ≥1/2,000 peripheral blood lymphocytes and found mostly or only in the CD45RO+ memory T cell subset. In the remaining five patients, a low (+ naive T cell subset. Evaluation of CTL effector frequency after bulk culture indicated that peptide-specific CTLs could be activated in all patients by using professional antigen-presenting cells as dendritic cells, but CTLp frequency determined the kinetics of generation of specificity and the final number of effectors as evaluated by both limiting dilution analysis and staining with HLA-A*0201-Melan-A/Mart-1 tetrameric complexes. Immunohistochemical analysis of 26 neoplastic lesions from the nine patients indicated absence of tumor regression in most instances, even in patients with an expanded peripheral T cell pool to Melan-A/Mart-1 and whose neoplastic lesions contained a high frequency of tetramer-positive Melan-A/Mart-1-specific T cells. Furthermore, frequent lack of a 'brisk' or 'nonbrisk' CD3+CD8+ T cell infiltrate or reduced/absent Melan-A/Mart-1 expression in several lesions and lack of HLA class I antigens were found in some instances. Thus, expansion of peripheral immune repertoire to Melan-A/Mart-1 takes place in some metastatic patients and leads to enhanced CTL induction after antigen-presenting cell-mediated selection, but, in most metastatic lesions, it does not overcome tumor escape from immune surveillance.",
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AU - Molla, Alessandra

AU - Mortarini, Roberta

AU - Tragni, Gabrina

AU - Bersani, Ilaria

AU - Di Nicola, Massimo

AU - Gianni, Alessandro M.

AU - Pilotti, Silvana

AU - Dunbar, Rod

AU - Cerundolo, Vincenzo

AU - Parmiani, Giorgio

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