[CITATION][C] CTLA-4 blockade: unveiling immune regulation

G Dranoff - Journal of clinical oncology, 2005 - ascopubs.org
G Dranoff
Journal of clinical oncology, 2005ascopubs.org
To maintain tissue homeostasis under the duress of infection or injury, the immune system is
endowed with a diverse repertoire of soluble and cellular effectors. The innate response,
composed of granulocytes, macrophages, dendritic cells, natural killer cells, and
complement, is rapidly triggered into action, detecting tissue disturbance through a set of
germline-encoded pattern recognition receptors. The adaptive reaction, consisting of
antibodyproducing B cells and T lymphocytes, is slower to develop, but manifests exquisite …
To maintain tissue homeostasis under the duress of infection or injury, the immune system is endowed with a diverse repertoire of soluble and cellular effectors. The innate response, composed of granulocytes, macrophages, dendritic cells, natural killer cells, and complement, is rapidly triggered into action, detecting tissue disturbance through a set of germline-encoded pattern recognition receptors. The adaptive reaction, consisting of antibodyproducing B cells and T lymphocytes, is slower to develop, but manifests exquisite specificity and memory. These attributes reflect the requirement for expansion of rare clones harboring somatically rearranged immunoglobulin molecules or T-cell receptors specific for foreign proteins or processed peptides presented by major histocompatibility complex (MHC) molecules. These innate and adaptive responses are carefully orchestrated through soluble and membrane-bound regulators, resulting in the deployment of the most suitable effectors for containing the disorder, while minimizing tissue damage. Cancer cells similarly provoke immune recognition. In one pathway, innate effectors detect tumor cells directly. 1 Natural killer cells and phagocytes express NKG2D molecules that function as receptors for stress-related genes such as MICA and MICB, which are induced as a consequence of cellular transformation. Natural killer cells further scan for the loss of MHC class I molecules on the surface of tumor cells. Dendritic cells use a variety of scavenger receptors to result in the phagocytosis of dying tumor cells. The adaptive response exploits an indirect pathway, termed cross-priming, to recognize cancer cells. 2 In this mechanism, dendritic cells capture tumor cell debris, migrate to regional lymph nodes, and stimulate CD4+ and CD8+ T cells with tumor specificity. Primed T cells thereby acquire the capacity to detect tumor cells directly in a MHC-restricted fashion. CD4+ T cells also contribute to B-cell antibody production.
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