CBP/P300 BRD Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in TNBC.

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated CTLs. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC.

Unbiased metastatic niche-labeling identifies estrogen receptor-positive macrophages as a barrier of T cell infiltration during bone colonization.

Microenvironment niches determine cellular fates of metastatic cancer cells. However, robust and unbiased approaches to identify niche components and their molecular profiles are lacking. We established Sortase A-Based Microenvironment Niche Tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastatic colonization. SAMENT was applied to multiple cancer models colonizing the same organ and the same cancer to different organs. Common metastatic niche features include macrophage enrichment and T cell depletion. Macrophage niches are phenotypically diverse between different organs. In bone, macrophages express the estrogen receptor alpha (ERα) and exhibit active ERα signaling in male and female hosts. Conditional knockout of Esr1 in macrophages significantly retarded bone colonization by allowing T cell infiltration. ERα expression was also discovered in human bone metastases of both genders. Collectively, we identified a unique population of ERα+ macrophages in the metastatic niche and functionally tied ERα signaling in macrophages to T cell exclusion during metastatic colonization. HIGHLIGHTS: SAMENT is a robust metastatic niche-labeling approach amenable to single-cell omics.Metastatic niches are typically enriched with macrophages and depleted of T cells.Direct interaction with cancer cells induces ERα expression in niche macrophages. Knockout of Esr1 in macrophages allows T cell infiltration and retards bone colonization.

Nutrient Sensing in Macrophages Linked to Reorganized Tumor Vasculature.

Macrophages are plastic immune cells that have varying functions dependent on stimulation from their environment. In a recent issue of Immunity, Do and colleagues demonstrated that activating mechanistic target of rapamycin complex 1 signaling in tumor macrophages alters their metabolism, localization, and function. Specifically, these tumor macrophages promote vascular remodeling that develops a hypoxic environment toxic to cancer cells. This culminates in a tangible reduction in tumor burden in a murine model of breast cancer. Their findings reveal a unique strategy to promote vascular remodeling through macrophage polarization and thereby highlight the intimate connections between macrophage metabolism and function. Additionally, their model highlights parallels between tumor progression and wound healing contexts while emphasizing the amplified effect of small perturbations to a tumor ecosystem.

Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal.

Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting the overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain poorly understood. Herein, we characterized breast and lung cancer-induced BME shifts pre- and post-tumor removal. Remote tumors progressively lead to osteoprogenitor (OP) expansion, hematopoietic stem cell dislocation, and CD41- granulocyte-monocyte progenitor (GMP) aggregation. The tumor-entrained BME is characterized by co-localization between CD41- GMPs and OPs. OP ablation abolishes this effect and diminishes abnormal myeloid overproduction. Mechanistically, HTRA1 carried by tumor-derived small extracellular vesicles upregulates MMP-13 in OPs, which in turn induces the alterations in the hematopoietic program. Importantly, these effects persist post-surgery and continue to impair anti-tumor immunity. Conditional knockout or inhibition of MMP-13 accelerates immune reinstatement and restores the efficacies of immunotherapies. Therefore, tumor-induced systemic effects are initiated by OP-GMP crosstalk that outlasts tumor burden, and additional treatment is required to reverse these effects for optimal therapeutic efficacy.

Node foretold: Cancer cells in lymph node rewire the immune system to enable further metastases.

A Cell article reports that lymph node metastases can suppress the immune system, thereby promoting further cancer spread in mouse models; this is corroborated in patients as described in a letter in this issue of Cancer Cell. The lymph node thus actively generates a cancer-permissive environment and is an untapped target to manipulate the immune system.

Supercoiling and looping promote DNA base accessibility and coordination among distant sites.

DNA in cells is supercoiled and constrained into loops and this supercoiling and looping influence every aspect of DNA activity. We show here that negative supercoiling transmits mechanical stress along the DNA backbone to disrupt base pairing at specific distant sites. Cooperativity among distant sites localizes certain sequences to superhelical apices. Base pair disruption allows sharp bending at superhelical apices, which facilitates DNA writhing to relieve torsional strain. The coupling of these processes may help prevent extensive denaturation associated with genomic instability. Our results provide a model for how DNA can form short loops, which are required for many essential processes, and how cells may use DNA loops to position nicks to facilitate repair. Furthermore, our results reveal a complex interplay between site-specific disruptions to base pairing and the 3-D conformation of DNA, which influences how genomes are stored, replicated, transcribed, repaired, and many other aspects of DNA activity.

CHD4 regulates the DNA damage response and RAD51 expression in glioblastoma.

Glioblastoma (GBM) is a lethal brain tumour. Despite therapy with surgery, radiation, and alkylating chemotherapy, most people have recurrence within 6 months and die within 2 years. A major reason for recurrence is resistance to DNA damage. Here, we demonstrate that CHD4, an ATPase and member of the nucleosome remodelling and deactetylase (NuRD) complex, drives a component of this resistance. CHD4 is overexpressed in GBM specimens and cell lines. Based on The Cancer Genome Atlas and Rembrandt datasets, CHD4 expression is associated with poor prognosis in patients. While it has been known in other cancers that CHD4 goes to sites of DNA damage, we found CHD4 also regulates expression of RAD51, an essential component of the homologous recombination machinery, which repairs DNA damage. Correspondingly, CHD4 suppression results in defective DNA damage response in GBM cells. These findings demonstrate a mechanism by which CHD4 promotes GBM cell survival after DNA damaging treatments. Additionally, we found that CHD4 suppression, even in the absence of extrinsic treatment, cumulatively increases DNA damage. Lastly, we found that CHD4 is dispensable for normal human astrocyte survival. Since standard GBM treatments like radiation and temozolomide chemotherapy create DNA damage, these findings suggest an important resistance mechanism that has therapeutic implications.