CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions

Abstract

Exposure of lipopolysaccharide triggers macrophage pro-inflammatory polarization accompanied by metabolic reprogramming, characterized by elevated aerobic glycolysis and a broken tricarboxylic acid cycle. However, in contrast to lipopolysaccharide, CD40 signal is able to drive pro-inflammatory and anti-tumorigenic polarization by some yet undefined metabolic programming. Here we show that CD40 activation triggers fatty acid oxidation (FAO) and glutamine metabolism to promote ATP citrate lyase-dependent epigenetic reprogramming of pro-inflammatory genes and anti-tumorigenic phenotypes in macrophages. Mechanistically, glutamine usage reinforces FAO-induced pro-inflammatory and anti-tumorigenic activation by fine-tuning the NAD+/NADH ratio via glutamine-to-lactate conversion. Genetic ablation of important metabolic enzymes involved in CD40-mediated metabolic reprogramming abolishes agonistic anti-CD40-induced antitumor responses and reeducation of tumor-associated macrophages. Together these data show that metabolic reprogramming, which includes FAO and glutamine metabolism, controls the activation of pro-inflammatory and anti-tumorigenic polarization, and highlight a therapeutic potential of metabolic preconditioning of tumor-associated macrophages before agonistic anti-CD40 treatments.

A blueprint for tumor-infiltrating B cells across human cancers

“…CB839 treatment inhibited this trend, suggesting that GLS plays an essential role in B cell glutaminolysis. The metabolic fate of 13 C-labeled glutamine after R848 treatment confirmed that glutamine was catalyzed into glutamate (M5 labeled) and entered into the tricarboxylic acid (TCA) cycle through α-KG (M5 labeled), succinate (M4 labeled), fumarate (M4 labeled), pyruvate (M3 labeled), and lactate (M3 labeled), which is consistent with the reported glutaminolysis route ( 95 ) (Fig. 6E).…”

The role of glutamate and glutamine metabolism and related transporters in nerve cells

“…Subcutaneous tumors demonstrated a pronounced affinity for 18 F‐Gln 104 . Furthermore, research has shown that CD40 activation triggers fatty acid oxidation and glutamine metabolism, promoting the epigenetic reprogramming of pro‐inflammatory genes and the emergence of anti‐tumorigenic phenotypes in macrophages 105 . Compared to glycolysis, the process of the anaplerosis of glutamate plays a crucial role in the survival of tumor cells.…”

Good CARMA: Turning bad tumor‐resident myeloid cells good with chimeric antigen receptor macrophages

“…Macrophages respond to tissue damage, inflammation, cellular debris, and metabolic byproducts that are induced by cancer growth. As summarized in Table 1, TAMs play myriad roles in cancer pathogenesis: these include the promotion of inflammation, immunosuppression, 34–36 metabolic support for tumor growth, 37–39 degradation of the extracellular matrix (ECM) through the production of matrix metalloproteases and cathepsins, 40–42 promotion of epithelial–mesenchymal transition (EMT), 43 angiogenesis, 44,45 and metastatic spread 46,47 . The phagocytosis of apoptotic cells and activation of the Tyro3, Axl, and MerTK (abbreviated TAM) receptor tyrosine kinases together is termed efferocytosis; this process leads to the production of anti‐inflammatory signals, immunosuppression, and specific induction of exhaustion in or direct killing of CD8 T cells, 48–51 metabolic competition with immune effector cells and positive feedback loops with cancer‐associated fibroblasts (CAF) and regulatory T cells (Treg) 52–54 …”

“…Activation of CD40 leads to the production of IL‐12 and triggers fatty acid oxidation and glutamine metabolism, thus promoting epigenetic reprogramming to induce pro‐inflammatory gene expression and antitumor responses, particularly when combined with chemotherapy, VEGF blockade, or CSF1R inhibition 91–93 . Metabolic rewiring of TAMs is also seen upon stimulation with CpG (a TLR9 agonist) to overcome the inhibitory “do not eat me” signal 94,95 . TAMs can also be reprogrammed with TREM2 inhibition, 96 using pH‐sensitive nanoparticles to release IL‐12 within the acidic environment, 97 or treatment with small molecule kinase inhibitor; all of these interventions have been shown in preclinical models to result in TME inflammation, promote CD8 T‐cell activation and suppress tumor growth 98 .…”

“…[91][92][93] Metabolic rewiring of TAMs is also seen upon stimulation with CpG (a TLR9 agonist) to overcome the inhibitory "do not eat me" signal. 94,95 TAMs can also be reprogrammed with TREM2 inhibition, 96 using pH-sensitive nanoparticles to release IL-12 within the acidic environment, 97 or treatment with small molecule kinase inhibitor;…”