Ym1 is a stem cell secreted factor that augments NK cell killing of tumor cells (162.31)

Abstract

Abstract We previously observed that embryonic stem cell-derived hematopoietic progenitor cells (HPCs) were resistant to NK cells in vitro despite their poor expression of MHC antigens. In contrast, HPCs were readily deleted by NK cells in vivo. This discrepancy led us to study protein expression by HPCs pre and post-transplantation using proteomics. The rationale was that in response to serum cytokines in vivo, HPCs likely upregulated certain proteins that enhanced NK cell cytotoxicity. Upon sequencing, most of these proteins were determined to be housekeeping proteins except for one protein, which we identified as Ym1, also known as chitinase 3-like protein 3. Subsequently, recombinant Ym1 was generated in E. coli. Ym1 strongly enhanced NK cell cytotoxicity to HPCs in vitro by activating NK cells into the highly cytotoxic Mac1hi subsets. This process was APC-dependent, suggesting cross-presentation of IL-15 to NK cells by APCs. In vivo, Ym1 induced the emergence of mature CD27loMac1hi peripheral blood NK cells, which have been found to be most effective at lysing tumor cells. Further, Ym1 caused a significant increase in the production of IFN-γ, perforin and granzyme B. Indeed, Ym1 remarkably enhanced target cell killing by 3-4 fold, which is a novel finding that has promising implications for the application of Ym1 in cancer treatment.