Macrophage aids
As early as 2001, there were authors who combined several articles to review [1], "Macrophages can induce tumors and promote their progression. Macrophage aggregation suggests poor tumor prognosis; at the initial stage of tumor, macrophages Cells create an inflammatory environment that causes cell mutations and promotes their growth.
With the development of tumors, macrophages create a pre-metastatic niche in advance of the arrival of tumor cells in the site where the tumor is about to be transferred; in turn, macrophages play an important nutritional role in the initial proliferation after tumor metastasis. "The visible macrophages are really the accomplices of the tumor, helping the tumor to "occur, develop, and metastasize." People naturally hate it.
In fact, according to the type of activation of macrophages and their different roles in the tumor microenvironment, tumor-associated macrophages (TAM) are mainly classified into M1 type and M2 type macrophages. M1 type macrophages have an anti-tumor effect, which is capable of distinguishing between tumor cells and normal cells, and finally kills tumor cells by recognizing tumor cells. M2 macrophages mainly play a role in promoting tumor growth, invasion and metastasis [2].
"wall grass" macrophage
Fortunately, it has been found that the phenotype of macrophages can be transformed under certain conditions. This is mainly determined by the balance of stimulation and suppression signals. Under appropriate conditions, macrophages can be redirected and have anti-tumor activity.
Recently, the latest research results of the University of Pennsylvania research team were published in the famous journal Nature Immunology entitled "Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47?mediated 'don't-eat- Me' signal" [3].
Sputum tumor and CD47
The membrane-bound protein CD47, overexpressed by many cancers, is a "don't-eat-me" signal that inhibits the phagocytic activity of macrophages on the binding of SIRPα (signal regulatory protein alpha) receptors on phagocytic cells. Prevent macrophages from attacking them. Blocking CD47-SIRPα binding promotes macrophage phagocytosis of tumor cells and induces anti-tumor responses in a variety of xenograft models.
In the pancreatic ductal adenocarcinoma (PDAC) model, CD47 blockade as a monotherapy has shown modest anti-tumor efficacy. Re-inoculation of macrophage metabolism can overcome this signal. But researchers now say that blocking only inhibitory signals like CD47 is not enough to convince macrophages to attack cancer, and additional stimuli are needed to enhance the antitumor activity of macrophages. First, they need a signal to activate them (such as Toll-like receptor agonists). Later, a second signal (such as a CD47 inhibitor) can lower the threshold needed to fight cancer.
Dedicated to Zhaoan - CpG
"Tumor-associated macrophages are essential for anti-tumor responses to CpG activation." CpG (binucleotide) is a Toll-like receptor agonist that activates macrophages via CpG to stimulate macrophages. Changes in metabolism. It was also found that even if T cells are not required, it can rapidly induce tumor shrinkage and prolong the survival of experimental mice. Unexpectedly, the researchers found that "macrophage activation, even if it does not inhibit the loss of CD47, is sufficient for antitumor activity in PDAC."
(CpG treatment effectively inhibited tumor growth in two independent PDAC tumor models. Although the tumor eventually relapsed, CpG significantly prolonged overall survival)
(CpG stimulates macrophage antitumor activity in vitro and in vivo, independent of the anti-phagocytic signal CD47 expressed on PDaC cells)
The original macrophage "what to eat and what to eat"
The macrophage phenotype can be distinguished by its core metabolic processes. For example, M1 macrophages rely on glycolysis metabolism and reduce oxidative phosphorylation, while M2 macrophages undergo lipid de novo production and glutamate breakdown to support fatty acid oxidation (FAO). FAO and lipid metabolism are the basis for the anti-tumor function of multiple bone marrow subpopulations such as dendritic cells and bone marrow-derived suppressor cells.
To understand the metabolic determinants that control macrophage anti-tumor function, we used metabolomics and PDAC homology models to study macrophage phagocytosis of PDAC cells stimulated by TLR. The study reveals the novel role of metabolic pathways in regulating the anti-tumor function of macrophages and highlights the potential for targeting macrophage metabolism, which can be used in cancer cells to overcome the over-suppression signal by innate immune evasion.
Change to eat "Imperial Food" before recruiting
To understand the molecular basis of this phenomenon, the team tracked the metabolic activity of macrophages and determined that activated macrophages began to use glutamine and glucose to support their ability to phagocytose cancer cells. This integration of metabolic inputs is supported by carnitine palmitoyltransferase and adenosine triphosphate citrate lyase, which together confer macrophage anticancer ability to overcome inhibitory CD47 on cancer cells.
"The results confirm the importance of lipid metabolism as a major regulator of macrophage antitumor activity. Changes in lipid metabolism can alter plasma membrane properties in macrophages, and doing so gives them more efficient phagocytic cells. ability."
(CpG-induced antitumor activity)
(The fatty acid oxidation induced by CpG is essential for macrophage antitumor activity.)
"Macrophages need the right way to supply energy to phagocytose cancer cells. To do this, you need to change your metabolism to direct energy in the right direction. Metabolism will eventually cause macrophages to cross the don't-eat-me signal. The researchers said.
significance
"The results also highlight the importance of macrophage metabolic status in circumventing immune checkpoint signals. The significance of this is to expand the impact of immunotherapy and to identify macrophage metabolism as a new therapeutic target that must be properly linked. Enables macrophages to exert anti-tumor functions.” The central carbon metabolism of macrophages serves as a regulator of its anti-tumor function, including the ability to phagocytose tumor cells. The results suggest that central carbon metabolism is a new determinant and a potential therapeutic target for stimulating macrophage anti-tumor activity.
