Enhanced human lymphokine-activated killer cell function after brief exposure to granulocyte-macrophage-colony
C N Baxevanis1, G V Dedoussis, N G Papadopoulos
1Department of Immunology, Hellenic Anticancer Institute, Athens, Greece.
Insights
Granulocyte-macrophage-colony stimulating factor (GM-CSF) significantly enhances low-dose interleukin-2 (IL-2)-induced lymphokine-activated killer (LAK) cell activity in cancer patients. This approach may improve immunotherapy outcomes and reduce treatment costs and side effects.
Area of Science:
- Immunology
- Cancer Research
- Cell Therapy
Background:
- Lymphokine-activated killer (LAK) cell function is crucial for immunotherapy.
- Interleukin-2 (IL-2) is used to generate LAK cells, but high doses are costly and toxic.
- Investigating novel methods to enhance LAK cell induction is essential for improving cancer treatment.
Purpose of the Study:
- To evaluate the efficacy of granulocyte-macrophage-colony stimulating factor (GM-CSF) in augmenting LAK cell generation.
- To assess GM-CSF's ability to enhance LAK induction using low-dose IL-2 in cancer patients.
- To identify the specific cell types responsible for GM-CSF-mediated LAK enhancement.
Main Methods:
- Peripheral blood mononuclear cells (PBMC) were collected from cancer patients undergoing IL-2 immunotherapy.
- PBMC were incubated with low-dose IL-2 in the presence or absence of GM-CSF for 1 hour.
- LAK activity was assessed against allogeneic tumor cells and LAK-sensitive cell lines.
Main Results:
- GM-CSF (10-100 ng/ml) synergized with low-dose IL-2 to significantly increase LAK activity (up to three-fold) compared to IL-2 alone.
- Enhanced LAK activity was maintained at day 5 and was mediated by CD8+ cells.
- GM-CSF increased IL-2 receptor (R)+ and CD8+ cell percentages, but not CD56+ cells.
Conclusions:
- GM-CSF can effectively enhance IL-2-induced LAK activity in short-term cultures.
- This approach holds potential for improving clinical outcomes in cancer immunotherapy.
- Utilizing GM-CSF may reduce the high costs and toxic side effects associated with conventional IL-2/LAK cell therapy.
Background:
Lymphokine-activated killer (LAK) cell function can be generated in peripheral blood mononuclear cells (PBMC) after brief exposure of high dose interleukin-2 (IL-2) over the course of 1 or 2 days' culture in plain culture medium (IL-2-pulsed PBMC). The aim of the present study was to investigate the ability of granulocyte-macrophage-colony stimulating factor (GM-CSF) to augment LAK induction in low dose IL-2-pulsed PBMC derived from patients with cancer undergoing immunotherapy with IL-2.
Methods:
Peripheral blood mononuclear cells were collected from patients with cancer receiving a 5-day cycle of local (intraperitoneal or intrapleural) infusions with IL-2. The cells were incubated with IL-2 in the presence or absence of GM-CSF for 1 hour and then tested as effectors against allogeneic tumor cells and LAK-sensitive cell lines.
Results:
Granulocyte-macrophage-colony stimulating factor at doses between 10 and 100 ng/ml was synergized with low dose IL-2 (100 IU/ml) in the generation of LAK activity in PBMC. Lymphokine-activated killer cell-mediated cytotoxicity derived from PBMC cultures incubated with IL-2 and GM-CSF was significantly higher (up to three-fold) compared with that generated with IL-2 alone. The GM-CSF-induced enhanced LAK activity was maintained when tested at day 5. GM-CSF increased the percentages of IL-2 receptor (R) positive (+) and CD8+ cells in the IL-2-pulsed PBMC. In contrast to CD56+ cells, highly purified CD8+ cells isolated from PBMC pulsed with IL-2 and GM-CSF responded with increased LAK activity, thus representing the cell-type that mediates the augmenting effect of GM-CSF. Major histocompatibility complex (MHC) molecules or the CD3 surface antigens were not involved in the GM-CSF-mediated enhancement of LAK induction because anti-MHC class I and class II monoclonal antibodies (MoAb) or MoAb against the CD3 molecules remained without any effect in this system. The GM-CSF-mediated LAK-enhancement was IL-2-dependent because MoAb against IL-2 receptor completely inhibited the generation of LAK activity.
Conclusions:
The use of GM-CSF for the enhancement of IL-2-induced LAK activity in 1 hour cultures may improve clinical results in cancer immunotherapy. In addition, implementation of this procedure could eliminate the high cost of cell culture which usually accompanies IL-2/LAK cell therapy as well as eliminate the known toxic side effects associated with this kind of therapy.
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