Autologous tumor infiltrating T cells cytotoxic for follicular lymphoma cells can be expanded in vitro.
Follicular lymphomas (FLs) rarely induce clinically significant T-cell-mediated responses. We showed that freshly isolated tumor infiltrating T cells (T-TILs) lack tumor-specific cytotoxicity. Stimulation of these T cells with FL cells in the presence of interleukin-2 (IL-2) and/or costimulation via CD28 does not lead to T-cell activation and expansion. In contrast, when stimulated with FL cells preactivated via CD40, autologous T-TILs can be expanded by the addition of exogenous IL-2. These T cells can be further expanded in vitro by the addition of exogenous IL-4, IL-7, or interferon-gamma, but not IL-12. Once activated, these T cells showed FL-directed cytotoxicity in four of five patients tested. We concluded that autologous cytotoxic anti-FL-specific T cells exist, but can only be detected in vitro under optimized conditions for T-cell stimulation and expansion. This suggests that their frequency in vivo is either very low or that the microenvironment does not provide the necessary signals to activate these T cells. This model system allows dissection of the requisite conditions for activation and expansion of lymphoma-directed cytotoxicity and may permit expansion of previously activated cytotoxic T cells for adoptive transfer.
Schultze
J L
JL
Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Seamon
M J
MJ
Michalak
S
S
Gribben
J G
JG
Nadler
L M
LM
D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D002883:Chromosomes, Human, Pair 14 / Q000648:ultrastructure; D002887:Chromosomes, Human, Pair 18 / Q000648:ultrastructure; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D008224:Lymphoma, Follicular / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000473:pathology*; D014178:Translocation, Genetic
D007376:Interleukin-2; D015851:Interleukin-7; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma