Skewed T-cell differentiation in patients with indolent non-Hodgkin lymphoma reversed by ex vivo T-cell culture with gammac cytokines.
The unfavorable clinical evolution in indolent non-Hodgkin lymphomas suggests defective control of neoplastic growth by the immune system. To address this issue, we evaluated phenotype, function, and maturation profile of CD4(+) and CD8(+) T cells from peripheral-blood, lymph nodes, or bone marrow of patients with B-cell non-Hodgkin lymphoma (NHL) at diagnosis. T cells from these patients frequently showed an activated but apoptosis-prone phenotype with low frequency of tumor-reactive T cells showing a TH2/Tc2 functional profile in the response to autologous tumor. In peripheral blood or in lymph nodes and bone marrow, and, in comparison to healthy donors, patients' T cells showed a skewed differentiation toward Tnaive and Tcentral memory stages, with low expression of granzyme B and perforin. T-cell culture with autologous tumor in the presence of IL-2, IL-15, and autologous bone marrow-derived cells led to massive T-cell expansion and to differentiation of cytotoxic factor(+) CD8(+) T cells releasing IFN-gamma and killing autologous B-cell tumor in an HLA-class I-restricted fashion. These results suggest impaired T-cell differentiation to effector stage in patients with B-cell NHL, but indicate that T-cell responsiveness to gammac cytokines is retained, thus allowing to promote generation of antitumor T cells for immune intervention.
Anichini
Andrea
A
Human Tumor Immunobiology Unit, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Mortarini
Roberta
R
Romagnoli
Luca
L
Baldassari
Paola
P
Cabras
Antonello
A
Carlo-Stella
Carmelo
C
Gianni
Alessandro M
AM
Di Nicola
Massimo
M
D000328:Adult; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D016207:Cytokines / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D053631:Interleukin Receptor Common gamma Subunit; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020395:Receptors, Interleukin-7 / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016207:Cytokines; C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D020395:Receptors, Interleukin-7; D007371:Interferon-gamma