Cancer Immunity 3:4 (2003) - EDITOR'S VIEW LATEST PAPERS SEARCH for PAPERS Printer-friendly PDF Comment(s) > Considerations > The hypothesis > Testing the hypothesis > References > Contact author Cancer Immunity, Vol. 3, p. 4 (18 June 2003) Hypothesis: Controlled necrosis as a tool for immunotherapy of human cancer Pramod K. Srivastava Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT 06030, USA Keywords: cancer, immunotherapy, necrosis Considerations The number of ways in which cells die is broadly characterized into apoptosis and necrosis (see 1 for a more nuanced and accurate view). Apoptosis refers to programmed cell death, where exposure of a cell to events such as radiation, certain cytokines, or drugs leads to activation of a specific cascade of events that end in DNA fragmentation and a ‘clean’ death. The contents of the cell are not released into the external milieu but get packaged into apoptotic bodies which may be scavenged by neighboring phagocytes. End of story. Necrotic death on the other hand may result from unplanned events, such as lytic infection by a virus, loss of membrane permeability, mechanical tearing of a cell, etc. Such cell death leads to spilling of the cellular contents into the immediate milieu and is thus ‘not clean’. A number of recent studies ( 2, 3, 4) have shown that in addition to not being a clean death, necrotic cell death is also not a quiet death. It is heard by the immune system which responds to it through both of its major arms, the innate and the adaptive. Dendritic cells (DCs) and related cells, such as macrophages, are the key components of both arms of the immune system ( 5) and are the cell types that respond to necrotic cell death. DCs bear receptors for the abundant cellular contents released by necrotic cell death e.g. heat shock proteins (HSPs) ( 6, 7) and DNA ( 8) and respond to them in multiple ways. Engagement of the HSP receptors, and presumably of the DNA receptors on macrophages and DCs, signals the primordial NF-kappaB pathway so important in biology ( 9). Such engagement stimulates macrophages to secrete cytokines and chemokines, and DCs to show changes characteristic of maturation and migration to the draining lymph nodes ( 4, 10). The HSPs mediate another powerful reaction that engages the adaptive immune system. The major HSPs have been shown to be associated in vivo with a large repertoire of cellular peptides, including antigenic peptides generated by degradation of the proteins within a cell ( 11). When necrotic death leads to the release of these HSP-peptide complexes, they are taken up by the DCs through the HSP receptors mentioned earlier. The peptides chaperoned by the DCs get re-presented by the DCs by their MHC class I and II molecules which in turn stimulate the CD8+ and CD4+ T cells ( 11). Thus necrotic cell death engages the innate and adaptive components of the immune system. This mode of cell death can be utilized for the therapy of human cancer. HSPs constitute a, if not the, major component of the innate and adaptive immuno-stimulatory activity of necrotic cells. Indeed, the HSPs (or more accurately, HSP-peptide complexes) purified from cancers have proven their http://www.cancerimmunity.org/v3p4/030604.htm (1 of 5)