Reinstating endogenous antitumor immunity: The concept of therapeutic management of cancer

There is now increasing evidence to suggest that adaptive immunity plays a major role in regulating the growth of tumour cells. T cells play a major role in coordinating the immune response against tumourspecific antigens during tumour progression. While T cell activation depends on the initial tumour antigen-specific signal provided to the T cell receptors via the antigenloaded major histocompatibility complex (MHC) complex on dendritic cells (DCs), additional signals provided by costimulatory molecules fine-tune this response, determining its strength, nature and duration. To this end, the discovery of receptors regulating T cell activation against the autologous tumour was of paramount importance for understanding how cancer progresses under immunosurveillance. The CD28 co-receptor acts as a strong positive costimulatory receptor, and CTL antigen-4 (CTLA-4) as a potent co-inhibitory receptor. The programmed death 1 (PD-1) receptor: PD-Ligand (PD-L) pathway is another major receptor–ligand network that functions primarily to provide a co-inhibitory signal. PD1: PD-L interactions maintain peripheral tolerance and are exploited by tumours to evade immune eradication by memory T cells specifically recognizing tumour peptides [1]. As such, this pathway has emerged as a potential therapeutic target for enhancing the immune response. A second important discovery, which also sheds light to our understanding of tumour evolution, is presented by the “immunoediting” theory. According to this theory, the immune system “edits” the tumour immunogenicity, resulting in the promotion or suppression of tumour growth, a phenomenon [2]. As a result of its capacity to shape tumour immunogenicity, an additional role for the immune system has emerged, namely that of prognostic indicator. Studies by Galon et al. [3], initiated almost a decade ago, have demonstrated that the quantity, quality and spatial distribution of immune cells within the tumour has a greater prognostic value than the standard tumour staging based on tumour burden, infiltration of draining and regional lymph nodes by tumour cells, and evidence of metastases. This so-called “immunoscore” came to complete the immunoediting theory by increasing the knowledge of the immune events inside the tumours, and by better understanding, the immune architecture of these tumours, as well as the functional programs of their constituents, all of which complete the idea of how tumours evade from immunosurveillance. Forum of Clinical Oncology