The best example of a successful in-situ vaccination of cancer is the “abscopal” effect that sometimes (rarely) occurs after radiotherapy (RT) of one tumor lesion leading to immune elimination of distant non-radiated tumor lesions. Successful abscopal responses require immunological tumor cell death (necrosis). This is the death of cells that occurs with the disruption of the cell membrane and release of internal cell contents and danger signals into the microenvironment. This is opposed to the most common form of cell death, called apoptosis, whereby the internal cell components are sequestered from exposure to the immune system by protective membranes (non-immunological cell death) without danger signals.
The immunological cell death caused by RT releases ‘danger signals’ which create the inflammatory environment needed to program in-situ vaccination. Danger signals attract dendritic cells (DC) to the site of the lysed tumor which process released tumor antigens chaperoned on heat shock molecules and then mature to educate killer T-cells in the lymph nodes which are responsible for the abscopal effect mechanism.
DC process antigens and express them on their surface in the context of an MHC I molecule. Killer T-cells recognize these antigens expressed within the MHC I molecule and are then activated to search for cells which express the same antigen in the context of MHC I molecules through-out the body. Upon recognition of the cells expressing the target antigen, the killer cell initiates a program to kill the targeted cell.
The immune system is best equipped to eliminate foreign antigens and is programmed to suppress killing of self-tissues. Since tumor cells derive from self-tissues, they are difficult for the immune system to recognize. However, tumors are different from normal cells and within tumor cells there are unique antigens, called “neoantigens”. These neoantigens are chaperoned by special proteins called “heat shock proteins” or HSP. When a tumor cell is killed in a manner that causes the release of internal contents into the microenvironment, the neoantigens attached to the HSP are exposed to the immune system. Under these conditions, dendritic cells can uptake and process the chaperoned neoantigens and train killer T-cells to kill tumors which express the neoantigens in the context of MHC I surface molecules.
The innate immune system is the first line of defense against pathogens and most organisms have developed some form of innate immune response. When the skin or mucosa layer is broken, a complex biochemical and inflammatory signaling cascade consisting of lysozymes, complement, neutrophils, monocytes, macrophages, natural killer, and natural killer T-cells is initiated. Antigen presenting cells (APC), such as dendritic cells and macrophages, ingest and degrade the invading pathogen. In the presence of ‘danger’, the APC promote an adaptive immune response. APC are therefore considered the “bridge” between innate and adaptive immunity.
The adaptive immune system is often called to action when the innate immune system is unable to cope with the invading pathogen. Antigen presenting cells (APCs), which include dendritic cells, macrophages, and B lymphocytes, recognize non-self antigens and present these antigens via the major histocompatibility complex (MHC) Exogenous antigens, such as those from a bacterial infection, are presented by MHC-II and recognized by CD4 T-cells. CD4 T-cells have no phagocytic activity but play an active role in activation of macrophages, cytotoxic T cells, and natural killer cells. antigens, such as viral infection or tumor cells, are displayed by MHC-I and recognized by CD8 T-cells (killer cells). After clonal expansion, the killer cells provide specific immunity capable of ‘sterilizing’ the body of the diseased cell.