TIMP1 与 TIMP2 下调 TGF-β 诱导的 NK 细胞蜕膜样表型

Natural Killer (NK) cells have been found to be anergic, exhausted and pro-angiogenic in cancers. NK cell from healthy donors, exposed to TGF , acquire the CD56 bright CD9 + 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 TGF 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 TGF . 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 TGF induced NK cell polarization towards a decidual-like-phenotype. TIMP1 and TIMP2 counteracted the effect of TGF in increasing the percentage of CD56 bright, CD16 - , CD9 + and CD49a + , and restoring normal levels for TIMP 1 and 2 also inhibited decrease levels of the activation marker NKG2D induced by TGF and decreased the TGF upregulated exhaustion marker TIM-3.

NK cell degranulation capabilities against K562 cells were also decreased by TGF 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 TGF -induced NK cell polarization. Given the heterogeneity of released factors within the TME, it is clear that TGF 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.