Immuno-oncology: understanding the function and dysfunction of the immune system in cancer

Abstract

The immune system has the greatest potential for the specific destruction of tumours with no toxicity to normal tissue and for long-term memory that can prevent cancer recurrence. The last 30 years of immuno-oncology research have provided solid evidence that tumours are recognised by the immune system and their development can be stopped or controlled long term through a process known as immunosurveillance. Tumour specificity of the immune response resides in the recognition of tumour antigens. Viral proteins in tumours caused by viruses and mutated proteins from oncogenes or other genes, as well as nonmutated but abnormally expressed self proteins found on all tumours, have been shown to be good antigens and good targets for immunosurveillance. In many cancers, however, malignant progression is accompanied by profound immune suppression that interferes with an effective antitumour response and tumour elimination. Initially, most of the escape from immunosurveillance was ascribed to changes in the tumour cells themselves (loss of tumour antigens, loss of human leukocyte antigen molecules, loss of sensitivity to complement, or T cell or natural killer (NK) cell lysis), making them a poor target of an immune attack. However, it has become clear that the suppression comes from the ability of tumours to subvert normal immune regulation to their advantage. The tumour microenvironment can prevent the expansion of tumour antigen-specific helper and cytotoxic T cells and instead promote the production of proinflammatory cytokines and other factors, leading to the accumulation of suppressive cell populations that inhibit instead of promote immunity. The best described are regulatory T cells and myeloid-derived suppressor cells. Great conceptual and technical advances in the field of immuno-oncology over the past 30 years have provided us with the knowledge and techniques to develop novel immunotherapeutic approaches for the treatment of cancer. These include methods that enhance tumour immunity by blocking inhibitory pathways and inhibitory cells in the tumour microenvironment (e.g. antibodies against cytotoxic T-lymphocyte-associated antigen-4, programmed death 1 or its ligand programmed death ligand 1, or low-dose chemotherapy). Of equal importance, they include methods that can enhance the specificity of antitumour immunity by inducing the expansion of T cells and antibodies directed to well-defined tumour antigens (e.g. cancer vaccines, potent adjuvants, immunostimulatory cytokines). Even as monotherapies, these approaches are having a substantial impact on the treatment of some patients with advanced, previously untreatable, malignancies. Most exciting of all, these successes provide a rationale to expect that used in various combinations or earlier in disease, current and future immunotherapies may transform cancer treatment, improving a prognosis for many patients.

Figures

Figure 1

Janus was the Roman god of beginnings and transitions, depicted as two-faced since he looks to the future and the past. In the same way that the Janus principle can be used to illustrate the past accomplishments and future opportunities for scientific progress, the two faces could also be used to represent two sides of the same story; in this case, immune function/tumour rejection and immune dysfunction/tumour promotion. Via the process of immunosurveillance, the immune system can specifically identify and eliminate tumour cells on the basis of their expression of specific antigens (A). However, in cases where the immune system is not able to completely eliminate the cancer, a state of equilibrium develops whereby the tumour does not progress or further metastasize (B). Eventually, if the immune response fails to completely eliminate the tumour, cancer cells that can resist, avoid, or suppress the antitumour immune response are selected, leading to the tumour escape and a progressively growing tumour (C). In addition, infiltration of tumours by inflammatory immune cells can result in a state of chronic inflammation that maintains and promotes cancer progression and suppresses the innate anticancer immune response (D). The aim of immunotherapy is to modulate tumour immunity to change the ongoing immune response from tumour-promoting to tumour-rejecting, thus providing durable and adaptable cancer control (E).