Immunotherapy using drugs such as anti-PD-1/PD-L1 checkpoint inhibitors, is an anti-cancer strategy that can achieve durable clinical benefit in many cancer types, but in a manner that is limited to only some patients.
In fact clinical responses are often limited due to several mechanisms relating in the main to features in 1) cancer cells that make them invisible to immune attack and/or 2) changes in the tumor growth surroundings (commonly referred to as the tumor microenvironment) that create a barrier to effective immune cell infiltration and activation within tumors.
Alterations in cancer cell metabolism (the way cells process nutrients and various chemicals) are a feature of many tumors, also so referred to as “metabolic reprogramming”, have been implicated in cancers’ ability to evade immune control. The tumor microenvironment prevents successful immune cell attack on tumor cells due, at least partly, to lack of adequate nutrient supply and toxic product clearance.
This means that even if immune cells make it to the tumor site (which in many cases is a challenge in by itself), the conditions within the tumor microenvironment make it challenging for immune cells to survive or mount an effective attack against cancer cells (immune cells need to consume large amounts of nutrients to be able to work efficiently).
For example, cancer cells consume large amounts of glucose because they have increased levels of glucose consuming enzymes such as GLUT-1 and hexokinase-2. This consequently reduces the amount of glucose available to other cells in the tumor microenvironment, including cancer fighting immune cells which also rely on this key nutrient to carry out their role.
Another example is the scarcity of arginine, an amino acid that is key for immune cell activity, which is consumed through the enzyme arginase (produced by pro-tumor immune cells) hinders the ability of the so-called CD8 T cells (the cancer killing immune cells) to multiply and work effectively.
In a similar fashion, the reduced amounts of another important amino acid called tryptophan, through increased levels of the tryptophan consuming enzyme indoleamine 2,3-dioxygenase (IDO) (which is also present in tumor-promoting immune cells and some cancer cells) produces an unfavorable effect on cancer fighting immune cells, which become exhausted and obsolete.
The metabolic interactions that occur in the tumor microenvironment between cancer cells and immune cells form a key part of tumor overall biological behaviour and the way it eventually responds to immunotherapy.
It therefore follows that key metabolic enzymes, such as IDO and arginase, are being tested as targets for “metabolic conditioning” (or normalization) of the tumor microenvironment in order to enhance the effectiveness of the more conventional immunotherapeutic drugs, including anti-PD-1/PD-L1 checkpoint inhibitors, and extend their benefit to more patients.
