Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients

Abstract

Myeloid cells are key regulators of the tumor microenvironment, governing local immune responses. Here we report that tumorinfiltrating myeloid cells and circulating monocytes in patients with glioblastoma multiforme (GBM) express ligands for activating the Natural killer group 2, member D (NKG2D) receptor, which cause down-regulation of NKG2D on natural killer (NK) cells. Tumorinfiltrating NK cells isolated from GBM patients fail to lyse NKG2D ligand-expressing tumor cells. We demonstrate that lactate dehydrogenase (LDH) isoform 5 secreted by glioblastoma cells induces NKG2D ligands on monocytes isolated from healthy individuals. Furthermore, sera from GBM patients contain elevated amounts of LDH, which correlate with expression of NKG2D ligands on their autologous circulating monocytes. NKG2D ligands also are present on circulating monocytes isolated from patients with breast, prostate, and hepatitis C virus-induced hepatocellular carcinomas. Together, these findings reveal a previously unidentified immune evasion strategy whereby tumors produce soluble factors that induce NKG2D ligands on myeloid cells, subverting antitumor immune responses.LDH5 | glioma | cancer | tumor evasion

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

“…This is supported by previous findings showing that the number of tumor associated macrophages may be less significant than their gene expression and corresponding functions, 64,65 and suggests that identification of additional markers is required to define a phenotype associated with immunosuppressive functions. This model is supported by the various redundant mechanisms of immunosuppression in the TME, including soluble GBM tumor cell derived factors such as TGFβ, 66 LDH5, 5 IL-10, 67 and IDO. 68 Surface proteins including PD-L1, 69 and decreased MHC Class I expression on tumor cells 70 that likely influence TAM phenotypes and functions independently of CD163 expression are found in GBM, but not in the tumors of patients with low-grade gliomas.…”

“…Tumor associated macrophages (TAMs), accounting for ~ 20–30% of the cells in the GBM tumor mass, 2 express soluble factors and surface molecules that prevent immune surveillance by endogenous T and NK cells, and shut down crosstalk between the adaptive and innate immune systems. 3-5 Novel therapies that circumvent this suppressive milieu by blocking the recruitment or polarization of TAMs 6,7 are complicated by the paucity of markers that discriminate dysfunctional cells 8 and a poor understanding of the tumor-derived factors that influence their phenotype or trafficking. 9,10 Furthermore, gene expression analysis suggests that TAMs differ across grades of glioma 11,12 and regions within heterogeneous GBM tumors, 13 although it is not clear how these factors impact TAMs phenotypically and functionally.…”

A laktátdehidrogenáz (LDH) prognosztikai jelentősége az onkológiában

“…A tejsav fokozza az ARG1-génexpressziót makrofágokban, és gátolja a T-sejt-aktivációt és -proliferációt [65]. Kimutatták például, hogy a glioblastomasejtek által termelt LDHA, a tejsavtermelés jelentős fokozá-sával, megváltoztatja monocytasejtek daganatellenes immunválaszát [66]. Monocytákban a tejsav hatására a TNF, NF-κB és a pentraxin 3 (PTX3) gének downregulációját és az IL-23 upregulációját figyelték meg.…”

“…A természetes ölősejtek (NK) aktivitása a daganatból származó tejsavval vagy alacsony pH-val gátolható, amely folyamatot az NK aktivá-ciós receptor downregulációja közvetíti [71,72]. Kimutatták azt is, hogy például a glioblastomasejtek enzimatikusan aktív LDHA-t szekretálnak, amely a myeloid sejteken az NK Group 2D (NKG2D) ligand expresszióját indukálja, és ennek közvetítésével az NK-sejtek aktivitását csökkenti [66]. A daganatot infiltráló immunsejtekben a tejsav aktiválja az IL-23/IL-17 útvonalat a TLR-stimuláció hatására, amely elősegíti a helyi gyulladásos választ a T-helper (Th) 17/Th23 sejtek által, amely a daganatok kialakulásának és növekedésének kedvez [73].…”

The therapeutic potential of natural killer cells to target medulloblastoma

“…However, conditions in the tumor microenvironment, such as hypoxia, and glioma cell secretion of substances such as lactate dehydrogenase or the beta-galactoside-binding lectin, galectin-1, should downregulate the expression of NKG2DL [23][24][25]. These mechanisms and others might contribute to the immunoevasion of CNS tumor cells at the level of the NKG2D recognition pathway [23].…”