The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity

Abstract

NK cells have unique capabilities of recognition and destruction of tumor cells, without the requirement for prior immunization of the host. Maintaining tolerance to healthy cells makes them an attractive therapeutic tool for almost all types of cancer. Unfortunately, metabolic changes associated with malignant transformation and tumor progression lead to immunosuppression within the tumor microenvironment, which in turn limits the efficacy of various immunotherapies. In this review, we provide a brief description of the metabolic changes characteristic for the tumor microenvironment. Both tumor and tumor-associated cells produce and secrete factors that directly or indirectly prevent NK cell cytotoxicity. Here, we depict the molecular mechanisms responsible for the inhibition of immune effector cells by metabolic factors. Finally, we summarize the strategies to enhance NK cell function for the treatment of tumors.

Bioinformatic Analysis Reveals Central Role for Tumor-Infiltrating Immune Cells in Uveal Melanoma Progression

“…The enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes tryptophan degradation, an essential amino acid required for lymphocyte activation and proliferation, while producing highly suppressive kynurenine, resulting in suppression of NK and CD8+ T cell antitumor function [ 13 , 85 ]. Notably, the IDO expression can be induced by an immunosuppressive cytokine TGF- β as well as proinflammatory IFN- γ [ 86 ].…”

“…However, in the course of cancer microevolution, neoplastic cells undergo a series of adjustments adapting the cells to increased proliferation and selective pressure from the immune system [11,12]. These changes induce the formation of a hostile tumor microenvironment (TME) capable of inhibiting the immune cell effector function [11][12][13]. Hypoxia, immunosuppressive cytokines, metabolites, and other factors present in the TME can effectively dampen antitumor response, allowing for unrestricted tumor growth [12][13][14][15][16].…”

“…These changes induce the formation of a hostile tumor microenvironment (TME) capable of inhibiting the immune cell effector function [11][12][13]. Hypoxia, immunosuppressive cytokines, metabolites, and other factors present in the TME can effectively dampen antitumor response, allowing for unrestricted tumor growth [12][13][14][15][16]. Therefore, novel strategies emerging in cancer research are aimed at targeting the TME in order to restore proper immunosurveillance.…”

Estrogens and the Schrödinger’s Cat in the Ovarian Tumor Microenvironment

“…For instance, the soup of soluble factors in the microenvironment induces upregulation of the programmed death ligand 1 (PD-L1) on cancer and stromal cells; PD-L1 then binds to the matching PD-1 receptor expressed on CD8 + cells, ultimately leading to their exhaustion [ 140 , 141 , 142 ]. These factors contribute to the NKs’ depletion as well, by either lowering their attraction to the microenvironment or inducing in situ apoptosis [ 143 ], eventually granting the tumor an escape from immune destruction. Currently, several checkpoint inhibitors, such as anti-PD-1 and anti-PD-L1 inhibitors, are being tested as monotherapy and in combination with cytotoxic chemotherapy; unfortunately, only a modest benefit has been observed [ 144 , 145 , 146 ].…”

Prospects for NK Cell Therapy of Sarcoma

“…Because of these potent antitumor properties, intense studies are currently being carried out to use NK cells, induced pluripotent stem cell (iPSC)-derived NK cells, and the NK cell line NK-92 as novel therapeutic tools against cancer [ 25 , 26 , 27 ]. However, NK cell therapy faces many challenges, such as inadequate homing properties, hostile TME, or tumor immunoevasion [ 28 ].…”