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Cancer immunotherapy: advances and future challenges

Eliminating cancer by exploiting the immune system as a treatment modality is a long-standing idea that has now become a clinical reality. In 2011, the US Food and Drug Administration approved the first cancer immunotherapy: the inhibitory checkpoint inhibitor anti-CTLA4. The science underlying this treatment was recognized in the 2018 Nobel Prize for Medicine awarded to James Allison and Tasuko Honjo. We are now at the beginning of a revolution in cancer medicine with novel immune-based cancer treatments including antibodies, cytokines and molecules that boost anti-tumor immunity, in addition to adoptive cell therapy (ACT) that relies on the transfer of immune cells to attack tumors. Cancer immunotherapy has shown unprecedented success; however, despite some remarkable results, immunotherapy is only effective in a small proportion of patients and many types of malignancies remain resistant to immune-mediated treatment. This Immunology & Cell Biology Virtual Issue provides a detailed overview of how the immune system can be harnessed in immunotherapy against cancer and the issues that hinders its efficacy. Monoclonal antibodies are a major focus of cancer immunotherapy. The role of the Fc–FccR interaction in antibody-based immunotherapy is reviewed by Barnhart and Quigley. Antibody binding to FccR can impact treatment outcomes by triggering antibody-dependent cell death (ADCC) of tumor cells; however, it can also provoke deleterious side effects by depleting critical healthy cells. The impact of the antibody hinge length on ADCC is investigated by D’Eall and colleagues, using chimeric antibodies specific for tumor-expressed epidermal growth factor receptor (EGFR). In anti-checkpoint inhibitor therapy, blocking antibodies not only target and revive effector T cells, but also bind to regulatory T cells (Tregs). Sasidharan Nair and Elkord review the importance of Tregs in this therapeutic setting. ACT has proved to be an effective clinical approach to treat many types of cancer. Smith and Khanna describe how ACT can be used to treat virus-induced cancer and review recent data using allogenic T cells, rather than autologous T cells. This approach overcomes the difficulty in expanding virus-specific T cells from immunocompromised patients. Chimeric antigen receptor (CAR) T-cell therapy is a novel type of ACT using genetically engineered T cells that recognize tumor antigens in a MHC-independent manner. Yong and colleagues review CAR T-cell therapy against solid tumors and discuss the issues impairing the efficiency of CAR T cells in this setting and potential solutions to overcoming these limitations. Advances in understanding the complexity of Tcell immune responses against tumors provides support for the design of novel immunotherapy approaches. Chakraborty and colleagues have identified a novel population of CD8 Tregs that infiltrate tumors at early stages of tumor development. Furthermore, tumors frequently express MHC II and therefore can directly present tumor antigens to CD4 T cells. Using MHC IIdeficient melanoma cells, Shklovskaya and colleagues examine the role of direct versus indirect antigen recognition by CD4 T cells in tumor control. While conventional T cells are clearly important for antitumor immunotherapy, other T cells types are also