Mechanisms of tumor evasion from NKT cell-mediated immunosurveillance

Abstract

Natural killer T (NKT) cells are a unique subset of CD1d-restricted T cells that play an important role in mediating anti-tumor responses. NKT cells produce large amounts of cytokines and can directly mediate tumor cell lysis. However, NKT cells are numerically reduced and functionally impaired in cancer patients and the mechanisms by which tumor suppress NKT cell activation are poorly understood. Given that cancer cells possess epigenetic abnormalities, in addition to numerous genetic alterations, we hypothesize that tumors use epigenetic mechanisms to suppress anti-cancer immune responses by dysregulating antigen presentation and secreting soluble inhibitory factors. To test our hypothesis, lymphoma cells were pretreated with histone deacetylase inhibitors (HDACi) and then we assessed their ability to activate NKT cells. Treatment of B cell lymphomas with HDACi enhances anti-tumor immune responses by inducing CD1d-mediated antigen presentation, inhibiting STAT3, and subsequently, decreasing the production of STAT3-associated inflammatory cytokines. Moreover, we found that the enhanced immunogenicity observed following treatment with HDACi was HDAC2-dependent. Specifically, we performed chromatin immunoprecipitation (ChIP) to identify the HDAC that binds to the CD1D promoter. We found that HDAC2 binds to the CD1D promoter and negatively regulates CD1D transcription. In addition, we sought to investigate other mechanisms by which tumors suppress CD1d-mediated NKT cell activation. We found that, similar to lymphomas, ovarian cancers secrete molecules that can inhibit NKT cell activation. Additionally, we established a link between angiogenic factor secretion and suppression of antigen presentation, suggesting that existing anti-angiogenic therapies can positively impact anti-tumor immune responses. Thus, we identified cell- intrinsic and -extrinsic mechanisms by which tumors suppress CD1d-mediated antigen presentation, which can be targeted in an immunotherapeutic setting. Overall, our studies implicate roles of HDACi and anti-angiogenic therapies in immunotherapeutic approaches.