Abstract
Human lung tumors upregulate FGL1 (from Armed Forces Institute of Pathology via Wikimedia Commons)LAG-3 is a T-cell inhibitory receptor that also contributes to suppression mediated by regulatory T cells. A high-affinity ligand for LAG-3 is reported by Wang et al. to be fibrinogen-like protein 1 (FGL1), which is normally produced in the liver. T cells' effector functions are restored both in vitro and in vivo by blocking FGL1. When it is absent completely, mice acquire autoimmune syndromes. Upregulated FGL1 gene expression in solid tumors is also associated with poorer outcomes. Inhibiting both FGL1 and PD-1 pathways has synergistic effects, suggesting that combination blockade has antitumor therapeutic potential.Wang J, …, Chen L. Cell 2019 Jan;176:334–47.e12.Change can be good (by Lln.gyenes lfv via Wikimedia Commons)Patients with various solid tumors are currently being treated with immune checkpoint inhibitors, but not all responses are durable. The tumor mutational burden of multiple types of solid tumors was determined by sequencing 468 cancer-related genes from tumors and normal tissues. Patients with tumors of any type, except gliomas, have better overall survival after checkpoint blockade therapy if their mutational burden is in the upper 20th percentile for that tumor, which illustrates the prognostic value of this approach.Samstein RM, …, Morris LGT. Nat Genet 2019 Jan 14. DOI: 10.1038/s41588-018-0312-8.Regulating translation of PD-L1 (by LadyofHats via Wikimedia Commons)Immune evasion by tumors relies on changes in protein expression that were found to emanate from alterations in translation in a murine model of aggressive liver cancer. Tumors that both overexpress MYC and harbor the KRASG12D mutation produce PD-L1, translation of which is repressed in tumors harboring the KRASG12D mutation alone, because an upstream translational repressor is bypassed. Metastasis and immune evasion is dependent upon relief of this translational repression.Xu Y, …, Ruggero D. Nat Med 2019 Jan 14. DOI: 10.1038/s41591-018-0321-2.18th-century tumor educating a B cell (from J. Ashton's Chap-books of the Eighteenth Century, 1834)B cells accumulate in the draining lymph nodes (dLNs) of breast tumors. These B cells secrete IgG that targets the glycosylated form of heatshock protein HSPA4 on breast cancer cells. Ligation of HSPA4 induces the NF-κB pathway, which in turn activates the CXCR4-SDF1α chemotactic system, attracting cancer cells into the dLN and promoting metastasis. These events form a premetastatic niche in the dLNs and ultimately correlate with worse progression-free and overall survival.Gu Y, …, Cao X. Nat Med 2019 Jan 14. DOI: 10.1038/s41591-018-0309-y.STING agonist (by J. Couperus via flickr)Soluble (s)IL15/IL15R complexes are produced in the tumor microenvironment and enhance the numbers of infiltrating CD8+ T cells. Large established tumors are low in sIL15/IL15R, but by delivering STING agonists intratumorally as an inflammatory signal, soluble complexes are upregulated and released, which then drives tumor regression.Santana Carrero RM, …, Schluns KS. Proc Natl Acad Sci USA 2019 Jan;116:599–608.Tregs and conventional T cells use distinct subsets of TCRs (by Seanbatty via Pixabay)Regulatory T cells (Tregs) use a repertoire of T-cell receptors (TCRs) distinct from conventional T cells. Tumor-infiltrating Tregs from different tumor types are oligoclonal by deep sequencing of TCRB. The most expanded clones are tumor antigen–specific, shown by paired TCRA/B chain–transfection into autologous T cells. These Treg clones are also in circulation, but their TCRs are not found on other conventional T cells in the tumor or normal tissue.Ahmadzadeh M, …, Rosenberg SA. Sci Immunol 2019 Jan;4:eaao4310.
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