Abstract
The immune system has evolved complex effector mechanisms to protect the host against a diversity of pathogenic organisms and regulatory adaptations that can curtail pathological sequelae of inflammatory events, prevent autoimmunity, and assist in tissue repair. Cancers, by virtue of their local manifestations of tissue dysfunction and destruction, inflammation, and genomic instability, can evoke these protective mechanisms, which support the progression of tumors and prevent their immune eradication. Central to these processes is a subset of CD4+T cells, known as regulatory T (Treg) cells, that express the X chromosome–linked transcription factor FOXP3. In addition to their critical role in controlling autoimmunity and suppressing inflammatory responses in diverse biological settings, Treg cells are ubiquitously present in the tumor microenvironment where they promote tumor development and progression by dampening antitumor immune responses. Furthermore, Treg cells can directly support the survival of transformed cells through the elaboration of growth factors and interacting with accessory cells in tumors such as fibroblasts and endothelial cells. Current insights into the biology of tumor-associated Treg cells have opened up opportunities for their selective targeting in cancer, with the goal of alleviating their suppression of antitumor immune responses while maintaining overall immune homeostasis.
Highlights
A large body of research suggests that the tumor and immune cell interactions can affect the development of cancer and aid in its control (Dunn et al 2004)
Regulatory T (Treg) cells are a subset of CD4+ T cells that are requisite for control of autoimmunity, dampening excessive inflammation caused by the immune response to pathogens, and maintaining maternal-fetal tolerance ( Josefowicz et al 2012)
We provide an overview of Treg cell biology, discuss the features and roles of Treg cells in the tumor microenvironment (TME), and review the means by which they can be targeted for cancer immunotherapy
Summary
A large body of research suggests that the tumor and immune cell interactions can affect the development of cancer and aid in its control (Dunn et al 2004). The degree to which CTLA-4 antibodies deplete Treg cells in tumors and the contribution of this effect to www.annualreviews.org Regulatory T Cells in Cancer 467 Their overall therapeutic efficacy are likely influenced by host Fc receptor polymorphisms and the availability of effectors of antibody-dependent cellular cytotoxicity in the TME (Arce Vargas et al 2018). Tumor-resident Treg cells preferentially express high levels of OX40, and intratumoral delivery of anti-OX40 antibodies in mice leads to Treg cell depletion, which can be synergistic with other local immunotherapeutic approaches (Marabelle et al 2013, Piconese et al 2008) These observations are in contrast to what has been observed in human clinical trials, where there was no significant depletion of Treg cells but there was an increase in the proliferation of effector cells and some clinical responses (Curti et al 2013). Targeting Treg cells has been shown to markedly improve the therapeutic efficacy of radiotherapy and warrants further clinical investigation (Bos et al 2013)
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