Improving cancer immunotherapy by targeting tumor-induced immune suppression

The status of a host's immune response influences both the development and progression of a malignancy such that immune responses can have both pro- and anti-tumorigenic effects. Cancer immunotherapy is a form of treatment that aims to improve the ability of a cancer-bearing individual to reject the tumor immunologically. However, antitumor immunity elicited by the host or by immunotherapeutic strategies, can be actively attenuated by mechanisms that limit the strength and/or duration of immune responses, including the presence of immunoregulatory cell types or the production of immunosuppressive factors. As our knowledge of tumor-induced immune suppression increases, it has become obvious that these mechanisms are probably a major barrier to effective therapy. The identification of multiple mechanisms of tumor-induced immune suppression also provides a range of novel targets for new cancer therapies. Given the vital role that a host's immune response is known to play in cancer progression, therapies that target immune suppressive mechanisms have the potential to enhance anticancer immune responses thus leading to better immune surveillance and the limitation of tumor escape. In this review, mechanisms of tumor-associated immune suppression have been divided into four forms that we have designated as (1) regulatory cells; (2) cytokines/chemokines; (3) T cell tolerance/exhaustion and (4) metabolic. We discuss select mechanisms representing each of these forms of immuno-suppression that have been shown to aid tumors in evading host immune surveillance and overview therapeutic strategies that have been recently devised to suppress these suppressors.