There are many natural immune effector mechanisms for tumor detection and elimination.1 Regular function of these mechanisms helps prevent tumor growth and metastasis.1,2 By the time a tumor has developed, mechanisms are established that allow that tumor to avoid destruction by the immune system.
The discovery and development of immuno-oncology therapy in recent years represents a milestone in the treatment of cancer. Unlike traditional therapies that focus on attacking the tumor cells themselves, immuno-oncology focuses on mobilizing the patient's own immune cells to recognize and eliminate cancer cells.1,3-5 There are various immuno-oncology agents available and in development that can activate an immune response at various points along the immune cycle.3-5 However, treatment challenges persist and most cancer patients cannot benefit from current immuno-oncology therapies.
There are two components of the immune response that make up the immunity cycle4,5:
- Innate immune response
- The innate immune response is an antigen-independent response that is immediate and has no immunologic memory.4,5 Natural killer (NK) cells, dendritic cells (DCs), innate lymphoid cells (ILCs), and macrophages are the primary innate immune cell types.6,7
- Adaptive immune response
- The adaptive immune response is an antigen-dependent and antigen-specific response with the capacity for immunologic memory.4,5 T cells and B cells are the primary adaptive immune cell types.
The innate immune response is a critical first defense against microbes. It consists of a range of cell types and mechanisms that quickly respond to block microbial invasion. This system can detect the presence of a threat by recognizing microbial structures that are common among many types of invaders but not present in the host. The innate response is also important for activating and directing the adaptive response.
In a normal immune response:
- Damage-associated molecular pattern (DAMP) molecules released from microbes or infected cells activate innate immune cells that are capable of rapidly responding to the threat.8,9
- Stimulators of the innate immune response include proinflammatory cytokines (TNF-α, IL-1, IFN-α), bacterial and viral sensing pathways, and immune cell factors (CD40, antibodies bound to an invader). Inhibitors include IL-10, IL-4, and IL-13.4,10
- These same danger signals activate and mature DCs, the first step in the adaptive immune response.8,9
Steps in an adaptive immune response include:
- Antigen presentation to T cells by activated and mature antigen-presenting cells (APCs)
- Mature DCs capture and process proteins from the threat (antigens for the adaptive immune system to recognize) and migrate to draining lymph nodes.10
- Major histocompatibility complex (MHC) proteins on the surface of mature DCs present the captured antigens to the T-cell receptor on T cells4,5 along with the costimulatory proteins the T cells need to respond.
- MHC class I complexes are recognized by cytotoxic CD8+ T cells.11
- MHC class II complexes are recognized by CD4+ T cells.11
- T-cell expansion and migration
- T-cell killing
- Resolution of the response when the threat is no longer present