Citations

Abstract TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a co-inhibitory receptor, highly expressed by Tregs, and contributes to the suppressive function of Tregs by limiting pro-inflammatory Th1 and Th17 cell responses. Herein, we report that subsets of human regulatory B cells (Bregs) express surface TIGIT and can thus play a critical role in immune regulation. Using data from human B cell surface arrays and RNA-seq, we identified two major TIGIT+ human Bregs subsets, exhibiting CD24hiCD27+CD39hiIgD+IgMhiCD1chi marginal zone (MZ)-like and CD24hiCD27+CD39+IgD−IgM+CD1c+ memory Bregs. We further demonstrated that TIGIT+ Bregs were also capable of suppressing immune responses by their ability to express not only IL-10 and PD-L1, but also granzyme B and TGFb1. In addition, TIGIT+ Bregs can also suppress immune responses by altering dendritic cell functions. In line with these observations, liver allograft recipients with donor-specific alloantibody (DSA) had significantly lower numbers of TIGIT+ Bregs than those without DSA. Moreover, the frequency of TIGIT+ Bregs correlated with that of CD4+CD25+CD127lo Tregs, while it inversely correlated with the frequency of follicular helper T cells. We thus concluded that TIGIT+ Bregs play critical roles in immune regulation in liver allograft recipients.

Abstract The acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a critical problem in lung cancer clinic, but the underlying mechanisms have remained incompletely understood. Although the TKI-induced or -selected genetic changes are known to drive resistance, resistance also occurs in tumor cells without genetic changes through poorly-characterized processes. Here, we show that the extracellular matrix (ECM) from various components of the tumor microenvironment, including neighboring tumor cells and fibroblasts, may be the driver of resistance in the absence of genetic changes. Unlike genetic changes, which may evolve during relatively long time of chronic EGFR TKI treatment to drive resistance, briefly culturing on de-cellularized ECM, or co-culturing with the ECM donor cells, immediately confers resistance to tumor cells that are otherwise sensitive to EGFR TKIs. We show evidence that collagen in the ECM may be its primary constituent driving resistance, at least partly through the collagen receptor Integrin-β1. Intriguingly, such effect of ECM and collagen is dose-dependent and reversible, suggesting a potential clinic-relevant application for targeting this effect. Collectively, our results reveal that the stromal ECM acts as a microenvironmental cue promoting EGFR TKI resistance in lung cancer cells, and targeting collagen and Integrin-β1 may be useful for treating resistance, especially the resistance without clearly-defined genetic changes, for which effective therapeutics are lacking. Citation Format: Ting Zhang, Lixia Guo, Yuanyuan Wang, Tao Ren, Yanan Yang. Stromal extracellular matrix is a microenvironmental cue promoting resistance to EGFR tyrosine kinase inhibitors in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 122.

AbstractNOTCH1 is the prototype of the NOTCH family of single‐pass transmembrane receptors and regulates many basic processes during embryonic development and human pathogenesis. In core to NOTCH1 activation are proteolytic cleavages that release its intracellular domain (NICD1), which in turn translocates to the nucleus to regulate gene transcription. Macroautophagy (hereafter autophagy) has been shown to promote the degradation of NOTCH1, but the underlying mechanisms remain elusive. Here, we show that autophagy promotes the degradation of NOTCH1 by p62‐dependent binding between NICD1 and LC3, a component of the autophagosomes that execute autophagy. Strikingly, deleting any of the structural NICD1 domains fails to block the degradation of NICD1 by autophagy, and p62 binds to almost all these domains independently, indicating that p62 binds to multiple sites on NICD1 to promote its degradation. Intriguingly, inhibition of autophagy induces the accumulation of NICD1 in not only the cytoplasm but also the nucleus and increases the transcriptional activity of NICD1, and such regulation of nuclear NICD1 by autophagy is unique to NICD1 and not observed for all other NICDs (NICD2‐4). Collectively, our results suggest that autophagy tightly controls nuclear NOTCH1 activity through multiple p62 binding sites, and that modulating autophagy activity may be useful for treating NOTCH1 related human diseases. © 2018 IUBMB Life, 70(10):985–994, 2018

Abstract Lung cancer remains the leading cause of cancer-related death, partly due to the fact that most patients are diagnosed with metastatic disease, which is the main cause of death, yet effective therapeutics are lacking. Utilizing mouse models of metastatic lung adenocarcinomas, we report that the transcription factor GATA3 and its cofactor FOG2 play critical roles in lung adenocarcinoma metastasis by promoting the expression of the lysyl hydroxylase (LH) family members, which in turn regulate the tumorigenicity and motility of lung tumor cells through both EMT and EMT-independent mechanisms. In vivo, LHs are elevated in human lung adenocarcinomas and are associated with worse patient survival. Collectively, our data suggest that targeting LHs may be useful for treating metastatic lung cancer. Citation Format: Wei Liu, Ting Zhang, Lixia Guo, Yuanyuan Wang, Yanan Yang. Role of lysyl hydroxylases in metastatic lung cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B07.