Immune regulation in the tumor microenvironment and its relevance in cancer therapy

Cancer immunotherapy,including immune checkpoint blockade and CAR-T cell therapy,has introduced revolutionary approaches to treating patients with cancer.The success and hope of cancer immunotherapy have continuously stimulated high interest in dissecting immunotherapy resistance mechanisms,researching previously unknown therapeutic targets,and informing novel clinical trials in cancer therapy.The notion that the tumor microenvironment holds the key to understanding tumor immunity and developing novel immunotherapy has been well established in the field of tumor immunology and medical oncology[1].This special issue of Cellular&Molecular Immunology(CMI)compiles a series of review articles,presenting state-ofthe-art literature and concepts focused on several important aspects concerning the most recent advancement in immune sensitive and resistant mechanisms in the tumor microenvironment,and their relevance in cancer therapy.

Large tumor suppressor 2,LATS2,activates iNK in kinase-independent mechanism through ASK1

Apoptosis signal-regulating kinase 1 (ASK1)is an important mediator of the cell stress response pathways.Because of its central role in regulating cell death,the activity of ASK1 is tightly regulated by protein-protein interactions and post-translational modifications.Deregulation of ASK1 activity has been linked to human diseases,such as neurological disorders and cancer.Here we describe the identification and characterization of large tumor suppressor 2 (LATS2)as a novel binding partner for ASK1.LATS2 is a core kinase in the Hippo signaling pathway and is commonly downregulated in cancer.We found that LATS2 interacts with ASK1 and increases ASK1-mediated signaUng to promote apoptosis and activate the iNK mitogen-activated protein kinase (MAPK).This change in MAPK signaling is dependent on the catalytic activity of ASK1 but does not require LATS2 kinase activity. This work identifies a novel role for LATS2 as a positive regulator of the ASK1-MKK-JNK signaling pathway and establishes a kinase-independent function of LATS2 that may be part of the intricate regulatory system for cellular response to diverse stress signals.

NSD3S stabilizes MYC through hindering its interaction with FBXW7

The MYC transcription factor plays a key role in cell growth control. Enhanced MYC protein stability has been found to promote tumorigenesis. Thus, understanding how MYC stability is controlled may have significant implications for revealing MYC-driven growth regulatory mechanisms in physiological and pathological processes. Our previous work identified the histone lysine methyltransferase nuclear receptor binding SET domain protein 3 (NSD3) as a MYC modulator. NSD3S, a noncatalytic isoform of NSD3 with oncogenic activity, appears to bind, stabilize, and activate the transcriptional activity of MYC. However, the mechanism by which NSD3S stabilizes MYC remains to be elucidated. To uncover the nature of the interaction and the underlying mechanism of MYC regulation by NSD3S, we characterized the binding interface between both proteins by narrowing the interface to a 15-amino acid region in NSD3S that is partially required for MYC regulation. Mechanistically, NSD3S binds to MYC and reduces the association of F-box and WD repeat domain containing 7 (FBXW7) with MYC, which results in suppression of FBXW7-mediated proteasomal degradation of MYC and an increase in MYC protein half-life. These results support a critical role for NSD3S in the regulation of MYC function and provide a novel mechanism for NSD3S oncogenic function through inhibition of FBXW7-mediated degradation of MYC.

The NLRP4-DTX4 axis： a key suppressor of TBK1 and innate antiviral signaling

Cellular ＆ Molecular Immunology （2012） 9, 431-433; do i= 10.1038/c m i. 2012.49; published on li ne 15 October 2012 The innate immune system provides the first line of defense for protectionagainst pathogenic bacteria or viruses. The host ＇senses＇ pathogen infection by re- cognition of pathogen-associated molecular patterns via germ-line-encoded pattern- recognition receptors including Toll-like receptors, RIG-I-like receptors （RLRs）,