Differentiation of CD8+ T cells from tumor-invaded and tumor-free lymph nodes of melanoma patients: role of common gamma-chain cytokines.

Abstract

Differentiation of CD8(+) T cells at the tumor site toward effector and memory stages may represent a key step for the efficacy of antitumor response developing naturally or induced through immunotherapy. To address this issue, CD8(+) T lymphocytes from tumor-invaded (n = 142) and tumor-free (n = 42) lymph nodes removed from the same nodal basin of melanoma patients were analyzed for the expression of CCR7, CD45RA, perforin, and granzyme B. By hierarchical cluster analysis, CD8(+) T cells from all tumor-free lymph nodes and from 56% of the tumor-invaded lymph node samples fell in the same cluster, characterized mainly by CCR7(+) CD45RA(+/-) cytotoxic factor(-) cells. The remaining three clusters contained only samples from tumor-invaded lymph nodes and showed a progressive shift of the CD8(+) T cell population toward CCR7(-) CD45RA(-/+) perforin(+) granzyme B(+) differentiation stages. Distinct CD8(+) T cell maturation stages, as defined by CCR7 vs CD45RA and by functional assays, were identified even in melanoma- or viral Ag-specific T cells from invaded lymph nodes by HLA tetramer analysis. Culture for 7 days of CCR7(+) perforin(-) CD8(+) T cells from tumor-invaded lymph nodes with IL-2 or IL-15, but not IL-7, promoted, mainly in CCR7(+)CD45RA(-) cells, proliferation coupled to differentiation to the CCR7(-) perforin(+) stage and acquisition of melanoma Ag-specific effector functions. Taken together, these results indicate that CD8(+) T cells differentiated toward CCR7(-) cytotoxic factor(+) stages are present in tumor-invaded, but not in tumor-free, lymph nodes of a relevant fraction of melanoma patients and suggest that cytokines such as IL-2 and IL-15 may be exploited to promote Ag-independent maturation of anti-tumor CD8(+) T cells.

• Authors: Andrea Anichini, Alessia Scarito, Alessandra Molla, Giorgio Parmiani, Roberta Mortarini
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 171 Issue 4 Pg. 2134-41 (Aug 15 2003) ISSN: 0022-1767 [Print] United States
• PMID: 12902520 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Antigens, Viral
• CCR7 protein, human
• Epitopes, T-Lymphocyte
• IL2RG protein, human
• Interleukin Receptor Common gamma Subunit
• Interleukin-15
• Interleukin-2
• MART-1 Antigen
• MLANA protein, human
• Neoplasm Proteins
• Receptors, CCR7
• Receptors, Chemokine
• Receptors, Interleukin-7

Topics

• Antigens, Neoplasm
• Antigens, Viral (immunology)
• CD8-Positive T-Lymphocytes (cytology, immunology, metabolism, pathology)
• Cell Differentiation (immunology)
• Cells, Cultured
• Epitopes, T-Lymphocyte (immunology)
• Humans
• Interleukin Receptor Common gamma Subunit
• Interleukin-15 (physiology)
• Interleukin-2 (physiology)
• Lymph Nodes (cytology, immunology, pathology)
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism, pathology, virology)
• MART-1 Antigen
• Melanoma (immunology, pathology, virology)
• Neoplasm Proteins (immunology)
• Receptors, CCR7
• Receptors, Chemokine (biosynthesis)
• Receptors, Interleukin-7 (physiology)
• T-Lymphocyte Subsets (cytology, immunology, pathology)
• Tumor Cells, Cultured