NK Cell-Based Immunotherapy in Cancer Metastasis

Abstract

Metastasis represents the leading cause of cancer-related death mainly owing to the limited efficacy of current anticancer therapies on advanced malignancies. Although immunotherapy is rendering promising results in the treatment of cancer, many adverse events and factors hampering therapeutic efficacy, especially in solid tumors and metastases, still need to be solved. Moreover, immunotherapeutic strategies have mainly focused on modulating the activity of T cells, while Natural Killer (NK) cells have only recently been taken into consideration. NK cells represent an attractive target for cancer immunotherapy owing to their innate capacity to eliminate malignant tumors in a non-Major Histocompatibility Complex (MHC) and non-tumor antigen-restricted manner. In this review, we analyze the mechanisms and efficacy of NK cells in the control of metastasis and we detail the immunosubversive strategies developed by metastatic cells to evade NK cell-mediated immunosurveillance. We also share current and cutting-edge clinical approaches aimed at unleashing the full anti-metastatic potential of NK cells, including the adoptive transfer of NK cells, boosting of NK cell activity, redirecting NK cell activity against metastatic cells and the release of evasion mechanisms dampening NK cell immunosurveillance.

Mechanisms of Resistance to NK Cell Immunotherapy

“…Similarly, a decreased CD16 expression on NK cells and an impaired ADCC activity in patients with DLBCL at diagnosis were also observed [81]. Nevertheless, in spite of the fact that low NK cell numbers and activity have been associated with a hampered efficacy of NK cell-based therapies [17,18], the genetic influence in this scenario remains to be established.…”

“…Immunotherapy has been a recent major breakthrough in cancer treatment. Despite most of the current cancer immunotherapies being focused on T cells, NK cells are being increasingly considered to be a key target of immunotherapy (as recently reviewed in [17,18]) ( Table 1). For example, their ADCC function can contribute to the cytotoxic effects of different mAbs used in the therapy of many cancers, especially, but not limited to, those of hematological origin [18][19][20][21].…”

“…However, NK cells have some drawbacks as targets for immunotherapy. Despite some encouraging reports of clinical efficacy, infused NK cells showed limited expansion, persistence and capability of infiltrating solid tumors in vivo, which are major determinants of the clinical response [17,18,56,57]. In order to enhance their expansion and activation, NK cells need to be pre-activated with cytokines or feeder cells (Table 1) [58].…”

“…Moreover, B cells in the germinal centers of lymph nodes receive survival signals, rendering them more resistant to rituximab. In fact, NK cells are more efficient at eliminating blood cancer cells, small tumors and metastases than large solid tumors [17,18,57]. This clearly means that the tumor microenvironment is a major barrier to the success of NK cell anti-tumor therapies.…”

Synthesis of Novel 2-(Isopropylamino)thiazol-4(5H)-one Derivatives and Their Inhibitory Activity of 11β-HSD1 and 11β-HSD2 in Aspect of Carcinogenesis Prevention

“…On the other hand, in the process of neoplasm, effective recognition of pathological changes by the immune system is a key phenomenon in therapy and stopping the development of the disease. Particularly high activity of NK cells (Natural Killer) inhibits the formation and development of metastases in patients through the activation of NKG2D and DNAM-1 receptors [ 16 ]. The 11β-HSD1 activity appears to be directly related to the level of NK cells.…”