“Anergy” is a commonly used term in immuno-oncology, particularly in conjunction with T cells. So, what exactly does it mean and in what context is it used? The dictionary defines it as the “absence of the normal immune response to a particular antigen or allergen.” A simpler, one-word alternative is “tired” or, the exact opposite of energetic.
Robin Williams is/was energetic, while Sleeping Beauty is anergic (adjective). T cells that are anergic are tired (the T, in this case, is for tired). In fact, they are exhausted and depressed so much that they shirk their normal responsibilities, including the elimination of tumor cells, which consequently get a free pass. Normally, the immune system is on the lookout for trouble and spoiling for a fight, but anergic T cells are too tired and too dysfunctional to respond. They don’t salsa, they siesta. And, of course, while the T cells are away, the tumor will play (as in progress or spread).
So how do tumors (and other chronic diseases) manage to export anergy, which is a normal physiologic mechanism that prevents autoimmunity, to T cells? Several mechanisms are in play:
- Increased expression of immune checkpoint receptors on T cells such as PD-1, CTLA-4, Tim-3, and LAG-3. In general, the more of these inhibitory immune checkpoint receptors that are present on T cells in response to immunosuppressive factors present in the tumor environment, the more anergic they are. Antibodies that target these checkpoint receptors so-called immune checkpoints, like pembrolizumab (Keytruda), nivolumab (Opdivo) and ipilimumab (Yervoy), have revolutionized the treatment of cancer and demonstrated that the anergic state is reversible
- Inhibitory stromal cells in the tumor environment or tumor microenvironment (TME). All tumors, benign and malignant, have two basic components: the parenchyma (cancer cells) and the supportive stroma made up of connective tissue, blood vessels and inhibitory cells in which the cancer cells of the parenchyma are dispersed. These inhibitory cells include Tregulatory cells (Tregs), tumor associated macrophages (TAMs), myeloid derived stem cells (MDSCs), cancer-associated fibroblasts and adipocytes, and endothelial cells.
- Suppressive soluble molecules that are present in the TME. These molecules include IL-10, type I interferons, IDO, adenosine, VEGF-A, TGFβ, and IL-35Suppressive soluble molecules that are present in the TME. These molecules include IL-10, type I interferons, IDO, adenosine, VEGF-A, TGFβ, and IL-35
- Competition with tumor cells for essential nutrients like glucose. The reduction of glucose causes T cell dysfunction and impairs the immune response. In addition to nutrients like glucose, the lactic acid, low pH, and low oxygen (hypoxia) that are present in the TME lead to anergy
In summary, anergy is reversible. The combination of immunotherapies such as checkpoint inhibitors, RRx-001, which targets inhibitory stromal macrophages (TAMs) and AdAPT-001, which reduces the soluble suppressive molecule, TGFβ, may reverse T cell anergy and, thereby, restore antitumor immunity.