Immune checkpoint therapy-current perspectives and future directions.

Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.

ß-defensin-3 negatively regulates TLR4-HMGB1 axis mediated HLA-G expression in IL-1ß treated glioma cells.

The non-classical HLA class I antigen HLA-G contributes to immune escape mechanisms in glioblastoma multiforme (GBM). We have previously shown that IL-1ß-HIF-1α axis connects inflammatory and oncogenic pathways in GBM. In this study, we investigated the role of IL-1ß induced inflammation in regulating HLA-G expression. IL-1ß increased HLA-G and Toll like receptor 4 (TLR4) expression in a HIF-1α dependent manner. Inhibition of TLR4 signaling abrogated IL-1ß induced HLA-G. IL-1ß increased HMGB1 expression and its interaction with TLR4. Inhibition of HMGB1 inhibited TLR4 and vice versa suggesting the existence of HMGB1-TLR4 axis in glioma cells. Interestingly, HMGB1 inhibition prevented IL-1ß induced HLA-G expression. Elevated levels of HMGB1 and ß-defensin 3 were observed in GBM tumors. Importantly, ß-defensin-3 prevented IL-1ß induced HLA-G, TLR4, HMGB1 expression and release of pro-inflammatory mediators. Our studies indicate that ß-defensin-3 abrogates IL-1ß induced HLA-G expression by negatively affecting key molecules associated with its regulation.