T cell costimulation, checkpoint inhibitors and anti-tumor therapy

The hallmarks of the adaptive immune response are specificity and memory. The cellular response is mediatedby T cells which express cell surface T cell receptors (TCRs) that recognize peptide antigens in complex withmajor histocompatibility complex (MHC) molecules on antigen presenting cells (APCs). However, binding ofcognate TCRs with MHC-peptide complexes alone (signal 1) does not trigger optimal T cell activation. Inaddition to signal 1, the binding of positive and negative costimulatory receptors to their ligands modulates Tcell activation. This complex signaling network prevents aberrant activation of T cells. CD28 is the mainpositive costimulatory receptor on naı¨ve T cells; upon activation, CTLA4 is induced but reduces T cellactivation. Further studies led to the identification of additional negative costimulatory receptors known ascheckpoints, e.g. PD1. This review chronicles the basic studies in T cell costimulation that led to the discoveryof checkpoint inhibitors, i.e. antibodies to negative costimulatory receptors (e.g. CTLA4 and PD1) whichreduce tumor growth. This discovery has been recognized with the award of the 2018 Nobel prize in Physiology/Medicine. This review highlights the structural and functional roles of costimulatory receptors, themechanisms by which checkpoint inhibitors work, the challenges encountered and future prospects.

The ubiquitin-proteasome system.

The 2004 Nobel Prize in chemistry for the discovery of protein ubiquitination has led to the recognition of cellular proteolysis as a central area of research in biology. Eukaryotic proteins targeted for degradation by this pathway are first 'tagged' by multimers of a protein known as ubiquitin and are later proteolyzed by a giant enzyme known as the proteasome. This article recounts the key observations that led to the discovery of ubiquitin-proteasome system (UPS). In addition, different aspects of proteasome biology are highlighted. Finally, some key roles of the UPS in different areas of biology and the use of inhibitors of this pathway as possible drug targets are discussed.