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Abstract

Getting stabilized (from cegoh via Pixabay)A link has been found between oncogenic RAS signaling and increased immuno-suppressive expression of PD-L1. The mechanism relies on stabilization of the PD-L1 transcript, with RAS signaling culminating in phosphorylation and inactivation of TTP, a factor involved in degrading PD-L1 transcripts. As TTP inactivation causes accumulation of PD-L1 mRNA, interfering with the RAS pathway increases TTP binding to AU-rich elements of the transcripts, decreases PD-L1 protein production, and provides a means to enhance antitumor immunity.Coelho MA, …, Downward J. Immunity 2017 Dec 19;47:1083–99.e6.Resolvin D2 (from Roadnottaken via Wikimedia Commons)The goal of radio-, chemo-, and targeted therapy of tumors is to destroy tumor cells. However, the debris left from cell destruction can promote tumor growth through induction of local inflammation and cytokine release. Resolvins, as their name implies, quietly clean up and tune down inflammation. Addition of RvD1, RvD2, or RvE1 successfully cleared debris in a process dependent on phagocytosis by macrophages and reduction of inflammatory cytokine production.Sulciner ML, …, Panigrahy D. J Exp Med 2018 Jan 2;215:115–140.Shielded from removal (from LavaSnake via Wikimedia Commons)The proportion of patients that respond to PD-1 blockade remains low. PD-1 inhibits through recruitment of SHP2 and subsequent dephosphorylation of tyrosines involved in propagating TCR signals. SAP was found bound to intracellular PD-1 complexes and shielded phosphates from dephosphorylation by SHP2. Increased expression of SAP correlated with decreased inhibitory signaling through PD-1. Thus, therapeutically targeting SHP2 or SAP to increase T-cell responses could provide an approach to enhance responses to PD-1 blockade.Peled M, …, Mor, A. Proc Natl Acad Sci USA 2018 Jan 16;115:E468–77.Targeted IFN delivery plus TNF (from Cauwels et al.)Interferons can support antitumor activity, but have pleiotropic effects. Injection of exogenous IFN is associated with adverse side effects. Removing IFN's ability to bind to its widely expressed natural receptor, and providing it with an alternative segment that binds to Clec9, a DC-specific protein, allowed targeting of minute quantities of IFN to tumoral DCs without toxicity, and, with other therapies, completely eradicated tumors considered to be poorly immunogenic.Cauwels A, …, Tavernier J. Cancer Res 2018 Jan 15;78:463–74.Neutrophil enablers (from BruceBlaus via Wikimedia Commons)A hallmark of progression in many solid tumors is a preponderance of myeloid-derived cells and an increase in circulating myeloid-lineage cells. Nonmetastatic lung adenocarcinomas were found to disrupt bone marrow homeostasis in humans and mice. Osteocalcin+ osteoblasts increase in the bone marrow, and are responsible for the expansion of tumor-promoting SiglecFhigh neutrophils that accumulate in the tumor. The results highlight that cancer is a systemic disease, with cross-talk between lung tumors and bone enhancing tumor progression.Engblom C, …, Pittet MJ. Science 2017 Dec 1;358:eaal5081.Gastric tumor (from MF Press et al, Mol Cancer Therapeutics 2017)Although CTLA-4 acts as an inhibitor of antitumor responses, paradoxically, people with genetically-reduced expression of CTLA-4 have a greater risk for gastric cancer (GC). Insufficiency of CTLA-4 expression in mice instigates an inflammatory state that becomes premalignant and progresses to GC. The progression is not caused by dysregulation of microbiota, and can be transferred with spleen cells to Rag1-deficient mice. Th2 cytokines IL4 and IL13 were essential for tumorigenesis, inducing epigenetic disruptions in human GC, and Th1 or Th17 cells were not involved.Miska J, …, Chen Z. J Exp Med 2018 Jan 26. DOI: 10.1084/jem.20171971.