Metabolism has a recognized role in immune response, affecting immune cell activation, differentiation, and function. Metabolism also plays key roles in creating an immunosuppressive tumor microenvironment (TME) favorable to tumor growth or an immunoprotective TME that can suppress tumor growth.
“It has become increasingly clear that by targeting metabolism, we can affect both the tumor and the tumor microenvironment in ways that can have marked effects on anti-tumor immune responses,” said Jonathan Powell, MD, PhD, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine.
Powell moderated the major symposium on Cancer Immunometabolism and a companion panel discussion. Both focused on strategies to identify and target specific metabolic pathways to enhance cancer immunotherapy.
“Cancer, at its core, is a disease of dysregulated metabolism,” said Susan Kaech, PhD, NOMIS Center of Immunobiology and Microbial Pathogenesis, Salk Institute of Biological Studies. “There are metabolic checkpoints that give cancer cells growth and proliferative advantages and allow them to evade anti-tumor immunity. It may be possible to identify and target those checkpoints and affect the immunologic properties of T cells.”
More aggressive tumors alter the TME to make it more acidic, hypoxic, and nutrient poor, Kaech said. Metabolic adaptation to a changing TME contributes to T-cell dysfunction. The pro-tumor TME is also enriched in lipids, increasing T-cell uptake of oxidized LDL cholesterol and other lipids.
This uptake is modulated by CD36, which is upregulated in the pro-tumor TME and most abundantly expressed in exhausted T cells. The most lipid-active T cells are also PD-1-positive, which should highly activate immune cells.
“As T cells become more exhausted, they become less functional, less effective,” Kaech said. “If you block CD36, T cells improve their anti-tumor function. This seems to be a metabolic checkpoint in regulating anti-tumor function.”
Regulatory T cells play multiple roles in immunohomeostasis and are found in multiple tissues throughout the body, where they perform different roles in different tissues. In breast cancer, intratumoral Tregs upregulate lipid metabolism and CD36 expression. CD36 metabolic reprogramming may encourage the accumulation of Tregs in the TME, a poor prognostic marker.
“By knocking out a single gene for CD36 in a mouse model, we can see a significant reduction in tumor progression and impaired accumulation of intratumoral Tregs,” said Ping-Chih Ho, PhD, University of Lausanne Ludwig Institute for Cancer Research. “That suggested a vulnerability.”
An anti-CD36 antibody selectively diminishes intratumoral Tregs and improves anti-tumor response, Ho said.
“We believe we have identified a specific metabolic pathway that might help to treat a variety of solid tumors,” he said. “The combination of anti-CD36 and anti-PD-1 is more effective than any other treatment we have seen in this mouse model. We are hoping to move to human tumors.”
Powell is pursuing a similar metabolic approach by targeting glutamine. A targeted prodrug of 6-Diazo-5-oxo-L-norleucine (DON) can effectively downregulate glutamine metabolism to inhibit tumor growth and prolong survival in a mouse model by altering the TME to create more favorable anti-tumor conditions.
“We cured mice of their cancer,” Powell said. “We had never seen that before with a single drug.”
Glutamine blockade enhances the infiltration and proliferation of CD8+ tumor infiltrating lymphocytes and conditions CD8-TILs toward a highly activated, longer-lived phenotype, he said. In resistant tumor models such as B16 or 3LL, blocking angiogenesis greatly improves the efficacy of glutamine blockade.
“We’re even more excited about layering in PD-1 blockade,” Powell said.