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DISCUSSION Clinical application of NKT cells as therapy for malignancy is

DISCUSSION Clinical application of NKT cells as therapy for malignancy is usually critically dependent upon their activation and subsequent expansion in humans. With the development of therapeutic approaches with the potential to activate NKT cells (Nieda (Nieda (2002) decreased frequency and absolute number of NKT cells was not seen in lung cancer patients. A likely explanation for this inconsistency is the inclusion of insufficient patients in this subgroup to detect a statistically significant difference, in view of the 60 lung cancer patients assessed in the previous study. As no studies to date have assessed the numbers of NKT cells in breast malignancy patients we have, for the first time, exhibited a significantly reduced percentage of NKT cells in this malignancy group. Reasons for the observed reductions in breast malignancy and melanoma patients are unknown. It is evident that this results are not simply a consequence of increased total CD3+ T cell numbers in either disease (Table 2). Contrary to previous studies, which have in majority assessed NKT cell levels pretreatment or without indicating prior treatment, we have taken into consideration potential effects of chemotherapy or radiation treatment on NVP-BGJ398 manufacturer NKT cell numbers. We have identified that radiation treatment may be directly responsible for the decreased NKT cell numbers in melanoma patients. It remains possible, however, that a disease-specific effect by melanoma NVP-BGJ398 manufacturer may still contribute to the observed reduction and although not examined in this study, decreases in NKT cell numbers could also be due to an accumulation of NKT cells at tumour sites, thus decreasing their overall number in the circulating PB. This, together with longitudinal studies, aimed at ascertaining whether the low NKT cells numbers in these patients predated the manifestation of cancer, would help further the understanding of the relationship between NKT cell numbers and cancer. There were insufficient subject numbers to ascertain treatment-related effects on NKT cells breast cancer patients, and indications that chemotherapy modulates NKT cell numbers in lung cancer patients cannot be conclusively determined with the subject numbers available in this subgroup. The effect of the ageing process on NKT cell numbers has only been assessed in a singly study (DelaRosa NKT expansion on every cancer subject involved, we cannot determine whether NKT cell expansion is reduced in every cancer type, or whether the overall result is influenced by one or several subgroups of cancer patients. Mechanisms of reduced responsiveness of NKT cells to expansion capacity is dependent upon both the number and stimulatory capacity of CDld antigen-presenting cells, reduced numbers of and/or functionally defective CDld APC may suppress NKT activation in cancer patients. Production of immunosuppressive factors by tumour cells or TGF-by CD3+ T cells or intrinsic defects to the NKT cells themselves may also inhibit their expansion potential (Tada expansion potential. It will be interesting to determine through clinical trials whether this translates to NKT cell expansion and whether this group of patients would benefit most from clinical interventions aimed at NVP-BGJ398 manufacturer the activation and expansion of NKT cells. In summary, our study demonstrates that NKT cell numbers and their activation and capacity can be modulated by both age and malignancy and in contrast to previous studies, conventional cancer treatment. Whilst further studies are required to determine both the stage at which treatment NVP-BGJ398 manufacturer or malignant disease leads to decreased NKT cell numbers and the mechanism by which cancer affects impacts NKT cell function, our results provide important information for the clinical trials involving activation or large-scale expansion of NKT cells. Acknowledgments We thank Nirmala Pondeja for assistaance with statistical analyses.. simply a consequence of increased total CD3+ T cell numbers in either disease (Table 2). Contrary to previous studies, which have in majority assessed NKT cell levels pretreatment or without indicating prior treatment, we have taken into consideration potential effects of chemotherapy or radiation treatment on NKT cell numbers. We have identified that radiation treatment may be directly responsible for the decreased NKT cell numbers in melanoma patients. It remains possible, however, that a disease-specific effect by melanoma may still contribute to the observed reduction and although not examined in this study, decreases in NKT cell numbers could also be due to an accumulation of NKT cells at tumour sites, thus decreasing their overall number in the circulating PB. This, together with longitudinal studies, aimed at ascertaining whether the low NKT cells numbers in these patients predated the manifestation of cancer, would help further the understanding of the relationship between NKT cell numbers and cancer. There were insufficient subject numbers to ascertain treatment-related Keratin 7 antibody effects on NKT cells breast cancer patients, and indications that chemotherapy modulates NKT cell numbers in lung cancer patients cannot be conclusively determined with the subject numbers available in this subgroup. The effect of the ageing process on NKT cell numbers has only been assessed in a singly study (DelaRosa NKT expansion on every cancer subject involved, we cannot determine whether NKT cell expansion is reduced in every cancer type, or whether the overall result is influenced by one or several subgroups of cancer patients. Mechanisms of reduced responsiveness of NKT cells to expansion capacity is dependent upon both the number and stimulatory capacity of CDld antigen-presenting cells, reduced numbers of and/or functionally defective CDld APC may suppress NKT activation in cancer patients. Production of immunosuppressive factors by tumour cells or TGF-by CD3+ T cells or intrinsic defects to the NKT cells themselves may also inhibit their expansion potential (Tada expansion potential. It NVP-BGJ398 manufacturer will be interesting to determine through clinical trials whether this translates to NKT cell expansion and whether this group of patients would benefit most from clinical interventions aimed at the activation and expansion of NKT cells. In summary, our study demonstrates that NKT cell numbers and their activation and capacity can be modulated by both age and malignancy and in contrast to previous studies, conventional cancer treatment. Whilst further studies are required to determine both the stage at which treatment or malignant disease leads to decreased NKT cell numbers and the mechanism by which cancer affects impacts NKT cell function, our results provide important information for the clinical trials involving activation or large-scale expansion of NKT cells. Acknowledgments We thank Nirmala Pondeja for assistaance with statistical analyses..