Anti-CD47 immunotherapy as a therapeutic strategy for the treatment of breast cancer brain metastasis.

The presence of cell surface protein CD47 allows cancer cells to evade innate and adaptive immune surveillance resulting in metastatic spread. CD47 binds to and activates SIRPα on the surface of myeloid cells, inhibiting their phagocytic activity. On the other hand, CD47 binds the matricellular protein Thrombospondin-1, limiting T-cell activation. Thus, blocking CD47 is a potential therapeutic strategy for preventing brain metastasis. To test this hypothesis, breast cancer patient biopsies were stained with antibodies against CD47 to determine differences in protein expression. An anti-CD47 antibody was used in a syngeneic orthotopic triple-negative breast cancer model, and CD47 null mice were used in a breast cancer brain metastasis model by intracardiac injection of the E0771-Br-Luc cell line. Immunohistochemical staining of patient biopsies revealed an 89% increase in CD47 expression in metastatic brain tumors compared to normal adjacent tissue (p ≤ 0.05). Anti-CD47 treatment in mice bearing brain metastatic 4T1br3 orthotopic tumors reduced tumor volume and tumor weight by over 50% compared to control mice (p ≤ 0.05) and increased IBA1 macrophage/microglia marker 5-fold in tumors compared to control (p ≤ 0.05). Additionally, CD47 blockade increased the M1/M2 macrophage ratio in tumors 2.5-fold (p ≤ 0.05). CD47 null mice had an 89% decrease in metastatic brain burden (p ≤ 0.05) compared to control mice in a brain metastasis model. Additionally, RNA sequencing revealed several uniquely expressed genes and significantly enriched genes related to tissue development, cell death, and cell migration tumors treated with anti-CD47 antibodies. Thus, demonstrating that CD47 blockade affects cancer cell and tumor microenvironment signaling to limit metastatic spread and may be an effective therapeutic for triple-negative breast cancer brain metastasis.

Metabolic Implications of Immune Checkpoint Proteins in Cancer.

Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.

Combination of the anthocyanidins malvidin and peonidin attenuates lipopolysaccharide-mediated inflammatory gene expression in primary human adipocytes.

We recently demonstrated that California table grapes and a methanol-extractable, polyphenol-rich fraction decreased adiposity, insulin resistance, or markers of inflammation in high-fat fed mice. Malvidin and peonidin glycosides were the 2 most abundant anthocyanins in the polyphenol-rich fraction. We hypothesized that a blood borne combination of anthocyanidins malvidin and peonidin derived from intestinal ß-glycosidase metabolism of these 2 anthocyanins are responsible, in part, for the beneficial health effects observed in vivo. Therefore, we supplemented primary human adipocytes with malvidin or peonidin, alone or together, followed by acute lipopolysaccharide (LPS) treatment. Neither peonidin nor malvidin alone consistently decreased the expression of several inflammatory genes. However, supplementing adipocytes with an equal combination of malvidin plus peonidin followed by LPS treatment decreased the mRNA levels of interleukin (IL)-6, IL-1ß, IL-8, monocyte chemoattractant protein-1, toll-like receptor-2, tumor necrosis factor alpha, cyclooxygenase-2, and interferon gamma-induced protein-10. The highest combination dose of malvidin plus peonidin decreased or increased the expression of protein tyrosine phosphatase-1B and hormone sensitive lipase, respectively, genes encoding proteins associated with insulin resistance or lipolysis. These data indicate that a combination of malvidin plus peonidin have potentiating interactions that reduce inflammatory gene expression; however, in vivo studies are needed to support these in vitro data.