Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Abstract

The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

Phase I/II Clinical Trial of the Anti-Podoplanin Monoclonal Antibody Therapy in Dogs with Malignant Melanoma

“…The clinical response of dog#3, categorized as WHO stage I, was SD. It is well known that the efficacy of cytotoxic antibodies depends on the number of tumor-infiltrating effector cells (e.g., NK cells, macrophages), and cytotoxic antibodies show stronger anti-tumor effects against tumors with a larger number of infiltrating effector cells [ 67 , 68 ]. In canine malignant melanoma, the number of infiltrating effector cells is inversely correlated with tumor stage [ 69 ].…”

Glycogen Synthase Kinase 3β in Cancer Biology and Treatment

“…Clinical trials have tested different NK cell-based therapies for cancer, particularly for hematological malignancies, but their efficacy was not as high as anticipated [227]. Therefore, increasing the activity of NK cells against cancer is a promising avenue for the clinical application of immunotherapy [228]. Recently, two groups showed that GSK3β inhibition in normal peripheral NK cells enhances their cytotoxic effects against acute myeloid leukemia (AML) cells [143,144].…”

Targeting NK Cell Checkpoint Receptors or Molecules for Cancer Immunotherapy

“…Although blockade of LAG-3 alone seemed to have no effect on NK cell lysis against various targets, several reports showed that chronic stimulation of NK cells could increase LAG-3 surface expression and that of other co-inhibitory receptors, which contributed to NK cell exhaustion and weakened the anti-tumor activity of NK cells. In this situation, blocking LAG-3 could restore NK cells' cytotoxic capacity ( 93 , 94 ). In a 4T1 mouse lung metastatic breast cancer model, lung infiltrating NK cells manifested a dysfunctional state, with impaired lytic activity and low capacity to produce IFN-γ, concomitant with increased expression of inhibitory receptors and the loss of activating receptors.…”