Transcription factors (TF) contain structured DNA-binding domains and intrinsically disordered low complexity activation domains (LCD). Using single-molecule imaging in live cells, Chong and colleagues demonstrated that TF-LCD interactions were transient, sequence-specific, and aggregated to form clusters. These “hubs” of high TF concentrations were associated with genomic DNA and occurred throughout the nucleoplasm. TF-LCD puncta interacted with RNA polymerase II and drove transactivation. Using EWS-FL1 as a model, they showed that EWS LCD-LCD interactions at GGAA microsatellites were dynamic, selective for binding partners, and could be disrupted by hexanediols. Phase separation was not seen with endogenous levels of LCDs, but was observed at TF hubs upon forced expression of LCDs, suggesting a pathological feature.
Expert Commentary: These findings represent an important advance to the understanding of gene regulation and offer opportunities to screen for inhibitors of LCD-LCD interactions.
CARM1 Is Essential for Leukemogenesis
Chromatin-modifying enzymes are emerging as new therapeutic targets in cancer. Greenblatt and colleagues had previously shown that the protein methyltransferase CARM1 is overexpressed in 70% of patients with acute myeloid leukemia. Here, they explored the role of CARM1 in normal hematopoiesis and leukemogenesis to identify a relevant therapeutic index. While deletion of CARM1 had only minimal effects on normal hematopoiesis, deletion dramatically attenuated growth of leukemia cells in vitro and in vivo. Further, this growth defect could be rescued by overexpressing wild-type CARM1 but not with a methyltransferase defective mutant, consistent with CARM1′s enzymatic activity being required for leukemogenesis. While similar effects were observed using CARM1 selective inhibitors, histone demethylation was unaffected, suggesting non-histone substrates as likely CARM1 targets in leukemia cells.
Expert Commentary: CARM1 is a novel, commonly overexpressed drug target in leukemia. Inhibition minimally affects normal hematopoiesis.
Combined IL6 and PD-L1 Blockade Abrogates Immunosuppression
Cancer immunotherapies have led to durable therapeutic responses in specific cancer types, however, a significant number of patients eventually develop resistance. Determining mechanisms of resistance to cancer immunotherapies will enable development of effective combination therapeutic strategies. Tsukamoto and colleagues show that anti-IL6 antibody treatment augmented Th1 responses, but in turn, upregulated expression of PD-L1 on melanoma cells through CD4+ T-cell–derived IFNγ. Conversely, treatment with anti-PD-L1 antibodies resulted in IL6 production by PD-1+ macrophages in the tumor microenvironment. This is consistent with a dramatic increase of circulating IL6 observed in certain populations of patients with melanoma treated with anti-PD-1 therapy, associated with a poor clinical response to this therapy. Combined blockade of IL6 signaling and PD-1/PD-L1 pathways disrupted the interplay between these immunosuppressive events, promoting synergistic antitumor effects.
Expert Commentary: This study sheds light on the complex multiple modal action of anti-PD-1/PD-L1 therapy and suggests a promising and feasible combinatorial approach to target mutually immunosuppressive cross-talk between PD-1/PD-L1 and IL6 signals.
Tsukamoto H, Fujieda K, Miyashita A, Fukushima S, Ikeda T, Kubo Y, et al. Combined blockade of IL-6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment. Cancer Research; Published first July 2, 2018; doi: 10.1158/0008-5472.CAN-18-0118.
Targeting ATR to Improve Immune Response after Radiation
Although radiation can enhance response to anti-PD-1/PD-L1 agents, radiation therapy can also be immunosuppressive. Vendetti and colleagues found the ATR inhibitor AZD6738 cooperated with radiation through both antitumor cytotoxicity and by increasing CD8+ T-cell activity in the tumor microenvironment (TME). In a subset of animals, the combination led to complete responses with durable immunologic memory in a T-cell–dependent manner. AZD6738 blunted radiation-induced PD-L1 expression on the tumor and decreased IFNγ-secreting CD8+ T cells that can also increase tumoral PD-L1 expression. Furthermore, the combination led to increased CD8+ T-cell effectors, decreased Tregs, and decreased exhausted T cells in the TME.
Expert Commentary: This study suggests that the combination of an ATR inhibitor with radiation enhances both radiation-induced tumor cytotoxicity and antitumor immune responses.
Tumor Cell-Intrinsic Factors Control Immunotherapy Responses
Although the immune system clearly modulates progression of pancreatic ductal adenocarcinoma (PDAC), the mechanisms remain poorly understood. Utilizing a genetically engineered mouse model of PDAC with defined initiating drivers, Li and colleagues generated subclonal lines from each tumor. Heterogeneity in the immune response to sublines enabled stratifying tumors based on high or low T-cell infiltration. Analysis of somatic copy number alterations and gene expression revealed a MYC-amplified transcriptional program that induced CXCL1 in tumors with low T-cell infiltration. CXCL1 enhanced myeloid cell infiltration at the expense of CD103+ antigen-presenting dendritic cells within the tumor microenvironment, blunting responses to immunotherapy.
Expert commentary: A subset of cells that make up a cancer can enforce an immunosuppressive tumor microenvironment. Approaches that disentangle the inherent heterogeneity of cancers can reveal hidden immunotherapeutic targets.
AMPK: A New Metabolic Target in Glioblastoma
AMP kinase (AMPK), a serine-threonine kinase involved in cellular energy homeostasis, is a bioenergetic sensor allowing stressed cells to respond to metabolic needs. The role of AMPK in cancer is controversial, with reports of both pro- and antitumorigenic functions. Chhipa and colleagues provide compelling evidence that in the context of glioblastoma, AMPK promotes survival through regulation of bioenergetics. Oncogenic stress activates AMPK, which may contribute to the constitutively high levels of AMPK found in glioblastoma. This leads to AMPK-dependent phosphorylation of the transcription factor CREB1, regulating HIF1α and GABPA transcriptional programs that in turn control glioblastoma bioenergetics.
Expert Commentary: The ability of glioblastoma cells to co-opt AMPK-dependent signaling pathways in response to oncogenic stress to promote survival provides a new therapeutic opportunity in this deadly disease. Currently, inhibitors of AMPK lack specificity, but this study supports their further development.
Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.