Background: Immune normalization has emerged as a new paradigm in immunotherapy, which is proposed in cancer patients instead of the traditional immune enhancement therapy. The immune normalization strategy may also be implemented in cancer prevention of sub-healthy individuals.Methods: We established in vitro cultured mixed-Natural Killer cells (NKM), which could be used to achieve immune normalization. We defined the sub-healthy individuals after analyzing the PD-1 ratio in PBMCs from 95 donors over 50 years of age.Results: NKM were composed by approximately 20% NK cells (CD3-CD16+ or CD56+), 30% NKT-like cells (CD3+CD16+ or CD56+) and other T cells. The in vitro cytotoxicity of NKM was ten times higher than the peripheral blood mononuclear cells (PBMC). NKM cytotoxicity was negatively correlated with the ratio of regulatory T cells (CD3+CD4+ T), and positively correlated with the ratio of NK cells, especially CD56brightCD16bright NK cells. We found the sub-healthy individuals displayed significantly higher ratio of CD3+PD-1+ T cells in PBMC (Ratio > 4%) and higher ratio of CD3+CD8+PD-1+ T cells in CD3+CD8+ T cells (Ratio > 10%) than the healthy controls. Then, we evaluated the potential clinical application of NKM therapy in one pancreatic cancer patient and four sub-healthy individuals.Conclusions: NKM therapy showed good tolerance and no side effects were found. In sub-healthy individuals, the ratio of CD3+PD-1+ T cells and CD3+CD8+PD-1+ T cells was significantly reduced after NKM treatment, which indicated that NKM therapy could potentially be used for cancer prevention and health care, thereby achieving the immune normalization.Trial registration: International Research Center for Regenerative Medicine, BIH-2018-1001. 01 August 2018, BOAO International Hospital.International Research Center for Regenerative Medicine, BIH-2018-1002. 01 August 2018, BOAO International Hospital.
“Immune normalization” has emerged as a new paradigm in immunotherapy, which is proposed in cancer patients instead of conventional “immune-enhancement” therapy. Immune normalization may also be implemented in cancer prevention of “sub-healthy” individuals. We established in vitro cultured mixed-natural killer (NKM) cells to achieve immune normalization. The in vitro cytotoxicity of NKM cells was tenfold higher than that of peripheral blood mononuclear cells (PBMCs). The cytotoxicity of NKM cells was negatively correlated with the proportion of T-helper cells (cluster of differentiation: CD3+CD4+ T), and positively correlated with the proportion of NK cells (especially CD56 bright CD16 bright NK cells). Then, we defined “sub-healthy individuals” after measuring Programmed cell death protein-1 (PD-1) expression in PBMCs from 95 donors aged > 50 years. Furthermore, we evaluated the potential clinical application of NKM-cell therapy in 11 patients with malignant lymphoma, one patient with pancreatic cancer, and four sub-healthy individuals. NKM-cell therapy elicited good tolerance and side-effects were not found. In sub-healthy individuals, the proportion of CD3 + PD-1 + T cells and CD3 + CD8 + PD-1 + T cells was reduced significantly after NKM-cell treatment. We demonstrated that a new method using NKM cells was safe and efficacious as adjuvant treatment for cancer patients as well as therapy for sub-healthy individuals. Normalization of the peripheral immune system through NKM-cell therapy could expand its scope of application in different disorders.
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