NK Cells in the Tumor Microenvironment as New Potential Players Mediating Chemotherapy Effects in Metastatic Melanoma

Abstract

Until the last decade, chemotherapy was the standard treatment for metastatic cutaneous melanoma, even with poor results. The introduction of immune checkpoints inhibitors (ICIs) radically changed the outcome, increasing 5-year survival from 5% to 60%. However, there is still a large portion of unresponsive patients that would need further therapies. NK cells are skin-resident innate cytotoxic lymphocytes that recognize and kill virus-infected as well as cancer cells thanks to a balance between inhibitory and activating signals delivered by surface molecules expressed by the target. Since NK cells are equipped with cytotoxic machinery but lack of antigen restriction and needing to be primed, they are nowadays gaining attention as an alternative to T cells to be exploited in immunotherapy. However, their usage suffers of the same limitations reported for T cells, that is the loss of immunogenicity by target cells and the difficulty to penetrate and be activated in the suppressive tumor microenvironment (TME). Several evidence showed that chemotherapy used in metastatic melanoma therapy possess immunomodulatory properties that may restore NK cells functions within TME. Here, we will discuss the capability of such chemotherapeutics to: i) up-regulate melanoma cells susceptibility to NK cell-mediated killing, ii) promote NK cells infiltration within TME, iii) target other immune cell subsets that affect NK cells activities. Alongside traditional systemic melanoma chemotherapy, a new pharmacological strategy based on nanocarriers loaded with chemotherapeutics is developing. The use of nanotechnologies represents a very promising approach to improve drug tolerability and effectiveness thanks to the targeted delivery of the therapeutic molecules. Here, we will also discuss the recent developments in using nanocarriers to deliver anti-cancer drugs within the melanoma microenvironment in order to improve chemotherapeutics effects. Overall, we highlight the possibility to use standard chemotherapeutics, possibly delivered by nanosystems, to enhance NK cells anti-tumor cytotoxicity. Combined with immunotherapies targeting NK cells, this may represent a valuable alternative approach to treat those patients that do not respond to current ICIs.

Altered Frequencies and Functions of Innate Lymphoid Cells in Melanoma Patients Are Modulated by Immune Checkpoints Inhibitors

“…Because of their localization within tissues and their capability to promptly react to activating stimuli, ILCs may be involved in an early stage of an immune response to cancer cells. While the role played by NK cells in melanoma is firmly established (23,24), our knowledge about the potential role of other ILC subpopulations is limited.…”

“…In turn, this suggests that Nivolumab might improve the function of ILC2s and CD117 + ILCs not by directly affecting the interaction between melanoma cells and ILCs but rather by disrupting additional interactions mediated by PD-1 in vivo. Melanoma TME is enriched with suppressive immune cell subsets expressing PD-L1, such as macrophages, myeloid-derived suppressive cells (MDSCs) and regulatory T cells (Tregs) (24,45). ILC2s activity has been shown to be limited by suppressive subsets through cell-to-cell contact (46)(47)(48)(49), while similar data on CD117 + ILCs are missing.…”

Venetoclax enhances the efficacy of therapeutic antibodies in B-cell malignancies by augmenting tumor cell phagocytosis

“…Historically, conventional chemotherapy has been described to directly induce death of malignant cells by intervening in cellular processes like DNA synthesis or replication. 35 However, increasing evidence suggests that the antitumor effects of several drugs can also rely on stimulation of the innate immune system by activating natural killer (NK) cells, 36 human complement, 37 or macrophages, 38 thus triggering an eradication of tumor cells. 39 Furthermore, combining cytotoxic drugs with antibodies can increase therapy effects compared with single treatments.…”

Exosomes: A potential tool for immunotherapy of ovarian cancer

“…In this way, we can use FasL inhibitor to reduce its toxic effect on melanoma cells. Researchers have studied the principle of NK-exosomes killing melanoma cells ( 206 ), and tested the tumor-suppressive effect of NK-exosomes in vivo using a mouse model. It was found that the tumor size of the NK exosome-treated group was significantly smaller than that of the control group, indicating that NK cell exosomes induced the apoptosis of melanoma cells in vitro .…”