Multifaceted nature of natural killer cells: Potential mode of interaction and shaping of stem cells

In this paper, we review a number of in vitro and in vivo studies regarding the efficacy of supercharged NK (sNK) cell therapy in elimination or treatment of cancer. We have performed studies using six different types of cancer models of oral, pancreatic, glioblastoma, melanoma, hepatic and ovarian cancers using hu-BLT mice. Our in vitro studies demonstrated that primary NK cells preferentially target cancer stem-like cells (CSCs)/poorly differentiated tumors whereas sNK cells target both CSCs/poorly-differentiated and well-differentiated tumors significantly higher than primary activated NK cells. Our in vivo studies in humanized-BLT mice showed that sNK cells alone or in combination with other cancer therapeutics prevented tumor growth and metastasis. In addition, sNK cells were able to increase IFN-γ secretion and cytotoxic function by the immune cells in bone marrow, spleen, gingiva, pancreas and peripheral blood. Furthermore, sNK cells were able to increase the expansion and function of CD8+ T cells both in in vitro and in vivo studies. Overall, our studies demonstrated that sNK cells alone or in combination with other cancer therapeutics were not only effective against eliminating aggressive cancers, but were also able to increase the expansion and function of CD8+ T cells to further target cancer cells, providing a successful approach to eradicate and cure cancer.

Supercharged NK Cell-Based Immuotherapy in Humanized Bone Marrow Liver and Thymus (Hu-BLT) Mice Model of Oral, Pancreatic, Glioblastoma, Hepatic, Melanoma and Ovarian Cancers

Kaur,

Jewett

2023

Role of Natural Killer Cells as Cell-Based Immunotherapy in Oral Tumor Eradication and Differentiation Both In Vivo and In Vitro

Kaur,

Jewett

2024

Despite advancements in the field of cancer therapeutics, the five-year survival rate remains low in oral cancer patients. Therefore, the effective therapeutics are needed against oral cancer. Also, several studies including ours, have shown severely suppressed function and number of NK cells in oral cancer patients. In this review, we discuss the approach to inhibit the tumor growth and metastasis by direct killing or NK cell-mediated tumor differentiation. This review also provides an overview on supercharging NK cells using osteoclasts and probiotic bacteria, and their efficacy as cancer immunotherapeutic in humanized-BLT mice.

Commentary: Ovarian Cancer: Path to Effective Treatments

Jewett,

Memarzadeh,

Kaur

2025

Despite advancements in cancer therapeutics such as checkpoint inhibitors and some targeted therapies, we have not achieved success in effectively treating ovarian cancer, since these therapeutics only benefit a subset of patients, and also provide short-term protection. The use of chemotherapy and radiation therapy can cause depletion and/or lack of immune cells' function. Chimeric antigen receptor T (CAR-T) cell therapy is found to be effective against several blood-based cancers, but limited success was seen against solid tumors. Targeting fewer antigens and significant side effects of therapy decreases the efficacy of CAR-T cells as immunotherapeutic in solid tumors, even though there is a great drive and significant effort to establish these therapies around the world. Bispecific and tri-specific antibodies have recently been advocated as effective cancer therapeutics. However, at present, these also suffer the fate of CAR-Ts since the loss of antigen on tumor cells will render these therapeutics ineffective. At present, we should design therapeutics that may have synergistic effects on killing/treating tumors. The only way we can establish that will be by learning the mechanisms of actions of immune therapeutics. Thus, advancement in the knowledge and effective strategies are required to develop cancer immuno-therapeutics. We have dedicated our efforts to understand the immunobiology of natural killer (NK) cells. One of our most important discoveries was demonstration of targeting of cancer stem-like cells (CSCs)/poorly differentiated tumors exhibiting lower major histocompability complex class I expression by the NK cells. In addition, we showed that supercharged NK (sNK) cells had great ability to target both CSCs/poorly differentiated and well differentiated ovarian tumors, whereas activated primary NK cells only targeted CSCs/poorly differentiated tumors. Therefore, the use of sNK cells in immunotherapy should result in effective elimination of heterogeneous populations of ovarian tumors.