Releasing the Brakes in Cancer

Abstract

Cancer is a heterogeneous group of diseases where abnormal cell growth with potential to invade other body parts takes control of normal homeostasis and becomes fatal if not timely and rightly treated. There are more than 100 types of cancers characterized so far and many yet to be identified. World Health Organization estimates, that worldwide in 2012 there were 4 million new cancer cases and 8.2 million cancer related deaths. Amongst various treatment options available for cancer, immunotherapy offers an approach where the focus is on enhancing or even inducing an antitumor immune response. Induction or enhancement of anti-tumor immune response is a formidable challenge in cancer because tumor cells use multiple immune evasion strategies and avoid being detected or eliminated by immune cells. Immune checkpoints refer to a network of stimulatory or inhibitory signaling pathways in the immune system which are critical in maintaining self-tolerance, limiting tissue damage and modulating the quality of immune response. Substantial evidence indicates that up regulation of inhibitory signaling molecules (CTLA - 4, PD - 1) by tumor cells subvert activation of tumor antigen specific Teffector cells. Therefore, blockade of inhibitory signaling pathways may be one potential way of revitalizing an exhausted immune response in tumors. Using this approach, antibodies directed against CTLA - 4 and PD - 1 have been shown an acceptable therapeutic benefit in preclinical models and cancer patients. This review will discuss the important immune checkpoints that have been identified critical to suppress anti-tumor immunity and have been exploited as drug targets.