TIMP1 and TIMP2 Downregulate TGFβ Induced Decidual-like Phenotype in Natural Killer Cells

Abstract

Natural Killer (NK) cells have been found to be anergic, exhausted and pro-angiogenic in cancers. NK cell from healthy donors, exposed to TGFβ, acquire the CD56brightCD9+CD49a+ decidual-like-phenotype, together with decreased levels of NKG2D activation marker, increased levels of TIM-3 exhaustion marker, similar to cancer-associated NK cells. Tissue inhibitors of metalloproteases (TIMPs) exert dual roles in cancer. The role of TIMPs in modulating immune cells is a very novel concept, and the present is the first report studying their ability to contrast TGFβ action on NK cells. Here, we investigated the effects of TIMP1 and TIMP2 recombinant proteins in hindering decidual-like markers in NK cells, generated by polarizing cytolytic NK cells with TGFβ. The effects of TIMP1 or TIMP2 on NK cell surface antigens were determined by multicolor flow cytometry. We found that TIMP1 and TIMP2 were effective in interfering with TGFβ induced NK cell polarization towards a decidual-like-phenotype. TIMP1 and TIMP2 counteracted the effect of TGFβ in increasing the percentage of CD56bright, CD16−, CD9+ and CD49a+, and restoring normal levels for TIMP 1 and 2 also inhibited decrease levels of the activation marker NKG2D induced by TGFβ and decreased the TGFβ upregulated exhaustion marker TIM-3. NK cell degranulation capabilities against K562 cells were also decreased by TGFβ and not by TIMP1 or TIMP2. TIMP1 treatment could partially restore degranulation marker CD107a expression. Treatment with recombinant TIMP-1 or TIMP-2 showed a trend, although not statistically significant, to decrease CD49a+ and TIM-3+ expression and increase NKG2D in peripheral blood NK cells exposed to conditioned media from colon cancer cell lines. Our results suggest a potential role of TIMPs in controlling the tumor-associated cytokine TGFβ-induced NK cell polarization. Given the heterogeneity of released factors within the TME, it is clear that TGFβ stimulation represents a model to prove TIMP’s new properties, but it cannot be envisaged as a soloist NK cell polarizing agent. Therefore, further studies from the scientific community will help defining TIMPs immunomodulatory activities of NK cells in cancer, and their possible future diagnostic–therapeutic roles.

The tumor innate immune microenvironment in prostate cancer: an overview of soluble factors and cellular effectors

“…Pro-angiogenic decidual-like NK (dNK-like) cells, characterized by the CD56 bright CD16 -VEGF high CXCL8 + IFN low subset, has been found in tumor infiltrating and circulating NK cells in NSCLC [153], pleural effusion of patients with metastatic cancers [154] and CRC patients [155]. These dNK-like cells have been found to be induced by TGFβ, as also confirmed by experimental in vitro models of TGFβ polarized cytolytic NK cells [149,153,154,156,157].…”

Tumor-associated macrophages related signature in glioma

“…MYL12A was proved to be involved in DNA damage repair and p53-driven apoptosis [ 28 ]. TIMP1 is member of natural inhibitors of the matrix metalloproteinases, which has the effect of controlling the polarization of Natural Killer cells induced by the tumor-related cytokine TGFβ [ 29 ]. CCDC109B was involved in the activation of cell death pathway.…”

“…CCDC109B was involved in the activation of cell death pathway. Xu et al showed that it plays an important role in mediating the migration and invasion of glioma cells induced by HIF1α [ 29 ].…”

Development and Validation of a Novel Prognostic Model for Glioma Based on Immune-Related Genes

“…TIMP1, CCL2 and SERPINE1 are the core nodes in the PPI network of 25 genes. The main function of metallopeptidase inhibitor 1 (TIMP1) is to inhibit the activity of metalloproteinases(MMP), which in turn exerts its pro-cancer effect [27]. TIMP1 is highly expressed in gliomas, it correlates with immune cell markers and m6A [28].…”