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Immunotherapy is proving to be an effective therapeutic approach in a variety of cancers. But despite the clinical success of antibodies against the immune regulators CTLA4 and PD-L1/PD-1, only a subset of people exhibit durable responses, suggesting that a broader view of cancer immunity is required. Immunity is influenced by a complex set of tumour, host and environmental factors that govern the strength and timing of the anticancer response. Clinical studies are beginning to define these factors as immune profiles that can predict responses to immunotherapy. In the context of the cancer-immunity cycle, such factors combine to represent the inherent immunological status - or 'cancer-immune set point' - of an individual.
Cancer is a genetic disease, with the growth of tumour cells initiated by mutations that activate oncogenic drivers. This process is combined with the genetic or non-genetic activation or inactivation of genes that promote or suppress the proliferation oftumours. In many cancers, oncogenesis is accompanied by the accumulation of mutations, which can provide a selective advantage to populations of cancer cells by increasing their degree of genetic diversity, accelerating their evolutionary fitness. Yet this diversity comes at a cost: the further a cancer cell diverges from a normal cell, the more likely it is to be recognized as foreign by the immune system. Although long considered a possibility, it has been demonstrated only in the past five years that the mutational burden of tumours contributes to immune recognition of cancer and that it may, at least partly, determine a person's response to cancer immunotherapy1-4.
The role of the immune system in cancer remained unappreciated for many decades because tumours effectively suppress immune responses by activating negative regulatory pathways (also called checkpoints) that are associated with immune homeostasis or by adopting features that enable them to actively escape detection5-7. Two such checkpoints, cytotoxic T-lymphocyte protein 4 (CTLA4) and programmed cell death protein 1 (PD-1), have garnered the most attention so far. CTLA4 is a negative regulator of T cells that acts to control T-cell activation by competing with the co-stimulatory molecule CD28 for binding to shared ligands CD80 (also known as B7.1) and CD86 (also known as B7.2). The cell-surface receptor PD-1 is expressed by T cells on activation during priming or expansion and...