Estrogens increase cancer cell efferocytosis to establish an immunosuppressive tumor microenvironment.

Phagocytic clearance of apoptotic cancer cells (efferocytosis) by tumor-associated macrophages (TAMs) contributes in a substantial manner to the establishment of an immunosuppressive tumor microenvironment. This puts in context our observation that the female steroid hormone 17β-estradiol (E2) facilitates tumor immune resistance through cancer cell extrinsic Estrogen Receptor (ERalpha;) signaling in TAMs. Notable was the finding that E2 induces the expression of CX3CR1 in TAMs to enable efferocytosis of apoptotic cancer cells which results in the suppression of type I interferon (IFN) signaling.

Estrogen signaling suppresses tumor-associated tissue eosinophilia to promote breast tumor growth.

Estrogens regulate eosinophilia in asthma and other inflammatory diseases. Further, peripheral eosinophilia and tumor-associated tissue eosinophilia (TATE) predicts a better response to immune checkpoint blockade (ICB) in breast cancer. However, how and if estrogens affect eosinophil biology in tumors and how this influences ICB efficacy has not been determined.

Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis.

Unlabelled: Triple-negative breast cancers (TNBC) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early-stage localized TNBC, the rate of distant recurrence remains high, and long-term survival outcomes remain poor. In a search for new therapeutic targets for this disease, we observed that elevated expression of the serine/threonine kinase calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) is highly correlated with tumor invasiveness.

Ca /Calmodulin Dependent Protein Kinase Kinase-2 (CaMKK2) promotes Protein Kinase G (PKG)-dependent actin cytoskeletal assembly to increase tumor metastasis.

Triple-negative breast cancers (TNBCs) tend to become highly invasive early during cancer development. Despite some successes in the initial treatment of patients diagnosed with early-stage localized TNBC, the rate of metastatic recurrence remains high with poor long-term survival outcomes. Here we show that elevated expression of the serine/threonine-kinase, Calcium/Calmodulin (CaM)-dependent protein kinase kinase-2 (CaMKK2), is highly correlated with tumor invasiveness.

Increased CaMKK2 Expression Is an Adaptive Response That Maintains the Fitness of Tumor-Infiltrating Natural Killer Cells.

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells facilitates M2 macrophage polarization and the development of myeloid-derived suppressor cells. Thus, there has been interest in developing CaMKK2 inhibitors as potential anticancer therapeutics.

The use of F-2-fluorodeoxyglucose (FDG) to label antibody fragments for immuno-PET of pancreatic cancer.

We generated F-labeled antibody fragments for PET imaging using a sortase-mediated reaction to install a transcyclooctene (TCO)-functionalized short peptide onto proteins of interest, followed by reaction with a tetrazine-labeled-F-2-deoxyfluoroglucose (FDG). The method is rapid, robust, and site-specific (radiochemical yields >25%, not decay corrected). The availability of F-2-deoxyfluoroglucose avoids the need for more complicated chemistries used to generate carbon-fluorine bonds.