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Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity.

Dahlberg CI, Sarhan D, Chrobok M, Duru AD, Alici E - Front Immunol (2015)

Bottom Line: However, NK cells represent only a minor fraction of the human lymphocyte population.Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients.Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors.

View Article: PubMed Central - PubMed

Affiliation: Cell Therapies Institute, Nova Southeastern University , Fort Lauderdale, FL , USA ; Cell and Gene Therapy Group, Center for Hematology and Regenerative Medicine (HERM), Karolinska University Hospital Huddinge, NOVUM , Stockholm , Sweden.

ABSTRACT
Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell-related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells may provide new possibilities for developing effective cancer immunotherapies by improving NK cell responses and making them less susceptible to the tumor microenvironment. Within this review, we will discuss clinical trials using NK cells with a specific reflection on novel potential strategies, such as genetic modification of NK cells and complementary therapies aimed at improving the clinical outcome of NK cell-based immune therapies.

No MeSH data available.


Related in: MedlinePlus

Immune evasion and immunosuppressive in the tumor microenvironment.
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Figure 2: Immune evasion and immunosuppressive in the tumor microenvironment.

Mentions: Natural killer cells can recognize and kill tumor cells in vitro. However, their efficiency in targeting solid tumors has not yet been fully acknowledged in the clinical setting even though endogenous and adoptively transferred activated NK cells can be detected in various tumors (122, 123). Nevertheless, not all tumors are equally well infiltrated by NK cells, and many of the infiltrating cells are dysfunctional (124–127). The failure of immune surveillance may in part be due to sustained immunological selection pressure on tumor cells resulting in the development of tumor escape variants that are in fact invisible to the immune system (Figure 2). In addition, cytotoxic function of immune effector cells is also largely suppressed in the tumor microenvironment (128), which could be explained by suppressive tumor-secreted factors as well as suppressive immune compartments, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAM), and regulatory T cells (Figure 2). One of the most studied immune-suppressive cell types associated with tumor progression is regulatory T cells (Treg), characterized by their expression of CD4, high CD25 (CD4+CD25+CD127low/neg) as well as the transcription factor forkhead box P3 (FoxP3) (129). The expansion of Treg population is promoted in different cancers and their accumulation correlates with impaired immune cell function and poor prognosis (130–135). In vitro, NK cells are suppressed by Treg cells in a cell contact-dependent manner where membrane-bound TGF-β is utilized to attenuate their cytotoxicity (136). In line with this, inverse correlation between NK cell activity and Treg cell expansion has been observed in patients with gastrointestinal stromal tumor (GIST) (136) as well as in hepatocellular carcinoma patients (137). Treg cells express the high-affinity IL-2 receptor alpha (CD25, IL-2Rα) and need IL-2 for their full function. Recent studies have indicated that NK cell proliferation, accumulation, and activation can be limited by Treg cells through hampering the availability of IL-2 released by activated CD4+ T cells (138, 139). Consequently, inadequate IL-2 levels in the tumor microenvironment limits the extent of NK cell-mediated tumor rejection.


Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity.

Dahlberg CI, Sarhan D, Chrobok M, Duru AD, Alici E - Front Immunol (2015)

Immune evasion and immunosuppressive in the tumor microenvironment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663254&req=5

Figure 2: Immune evasion and immunosuppressive in the tumor microenvironment.
Mentions: Natural killer cells can recognize and kill tumor cells in vitro. However, their efficiency in targeting solid tumors has not yet been fully acknowledged in the clinical setting even though endogenous and adoptively transferred activated NK cells can be detected in various tumors (122, 123). Nevertheless, not all tumors are equally well infiltrated by NK cells, and many of the infiltrating cells are dysfunctional (124–127). The failure of immune surveillance may in part be due to sustained immunological selection pressure on tumor cells resulting in the development of tumor escape variants that are in fact invisible to the immune system (Figure 2). In addition, cytotoxic function of immune effector cells is also largely suppressed in the tumor microenvironment (128), which could be explained by suppressive tumor-secreted factors as well as suppressive immune compartments, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAM), and regulatory T cells (Figure 2). One of the most studied immune-suppressive cell types associated with tumor progression is regulatory T cells (Treg), characterized by their expression of CD4, high CD25 (CD4+CD25+CD127low/neg) as well as the transcription factor forkhead box P3 (FoxP3) (129). The expansion of Treg population is promoted in different cancers and their accumulation correlates with impaired immune cell function and poor prognosis (130–135). In vitro, NK cells are suppressed by Treg cells in a cell contact-dependent manner where membrane-bound TGF-β is utilized to attenuate their cytotoxicity (136). In line with this, inverse correlation between NK cell activity and Treg cell expansion has been observed in patients with gastrointestinal stromal tumor (GIST) (136) as well as in hepatocellular carcinoma patients (137). Treg cells express the high-affinity IL-2 receptor alpha (CD25, IL-2Rα) and need IL-2 for their full function. Recent studies have indicated that NK cell proliferation, accumulation, and activation can be limited by Treg cells through hampering the availability of IL-2 released by activated CD4+ T cells (138, 139). Consequently, inadequate IL-2 levels in the tumor microenvironment limits the extent of NK cell-mediated tumor rejection.

Bottom Line: However, NK cells represent only a minor fraction of the human lymphocyte population.Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients.Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors.

View Article: PubMed Central - PubMed

Affiliation: Cell Therapies Institute, Nova Southeastern University , Fort Lauderdale, FL , USA ; Cell and Gene Therapy Group, Center for Hematology and Regenerative Medicine (HERM), Karolinska University Hospital Huddinge, NOVUM , Stockholm , Sweden.

ABSTRACT
Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell-related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells may provide new possibilities for developing effective cancer immunotherapies by improving NK cell responses and making them less susceptible to the tumor microenvironment. Within this review, we will discuss clinical trials using NK cells with a specific reflection on novel potential strategies, such as genetic modification of NK cells and complementary therapies aimed at improving the clinical outcome of NK cell-based immune therapies.

No MeSH data available.


Related in: MedlinePlus