Treg programming and therapeutic reprogramming in cancer.

Overcoming the immunosuppressive tumour microenvironment is the major challenge impeding cancer immunotherapy today. Regulatory T-cells (Tregs) are prevalent in nearly all cancers and, as immunosuppressive regulators of immune responses, they are the principal opponents of cancer immunotherapy. However, disabling Tregs systemically causes severe autoimmune toxicity, hastening the need for more selective methods to target intratumoural Tregs. In this review, we discuss a burgeoning new modality to specifically target tumour-infiltrating Tregs (TI-Tregs) by reprogramming their functionality from immunosuppressive to immune stimulatory within tumours. As the basis for therapeutic selectivity of TI-Tregs, we will focus on the defining features of Tregs within cancer: their highly activated state controlled by the engagement of key surface receptors, their distinct metabolic programme, and their unique transcriptional programme. By identifying proteins and pathways that distinguish TI-Tregs from other Tregs in the body, as well as from the beneficial antitumour effector T-cells within tumours, we highlight mechanisms to selectively reprogramme TI-Tregs for the treatment of cancer.

Moreno Ayala MA ，Li Z ，DuPage M 《-》

Phenotypic alterations, clinical impact and therapeutic potential of regulatory T cells in cancer.

Chaudhary B ，Abd Al Samid M ，al-Ramadi BK ，Elkord E ... -  《-》

Metabolic Regulation of Tregs in Cancer: Opportunities for Immunotherapy.

The promising outcomes observed in cancer immunotherapy are evidence that the immune system provides a powerful arsenal for the restriction of tumor outgrowth; however, the immunosuppressive tumor microenvironment (TME) is known to impair antitumor immunity and impede the efficacy of cancer immunotherapies. Regulatory T cells (Tregs), which prevent overt immune responses and autoimmunity, accumulate aberrantly in some types of tumor to suppress antitumor immunity and support the establishment of an immunosuppressive microenvironment. Ablation of Tregs has been shown to not only unleash antitumor immunity and interrupt formation of an immunosuppressive TME, but also lead to severe autoimmune disorders. Therefore, it is essential to develop approaches to specifically target intratumoral Tregs. Herein, we summarize the immunomodulatory functions of Tregs in the TME and discuss how metabolic regulation of Tregs can facilitate intratumoral Treg accumulation.

Wang H ，Franco F ，Ho PC 《Trends in Cancer》

Metabolic profiles of regulatory T cells in the tumour microenvironment.

Metabolic reprogramming of cancer cells generates a tumour microenvironment (TME) characterised by nutrient restriction, hypoxia, acidity and oxidative stress. While these conditions are unfavourable for infiltrating effector T cells, accumulating evidence suggests that regulatory T cells (Tregs) continue to exert their immune-suppressive functions within the TME. The advantages of Tregs within the TME stem from their metabolic profile. Tregs rely on oxidative phosphorylation for their functions, which can be fuelled by a variety of substrates. Even though Tregs are an attractive target to augment anti-tumour immune responses, it remains a challenge to specifically target intra-tumoral Tregs. We provide a comprehensive review of distinct mechanistic links and pathways involved in regulation of Treg metabolism under the prevailing conditions within the tumour. We also describe how these Tregs differ from the ones in the periphery, and from conventional T cells in the tumour. Targeting pathways responsible for adaptation of Tregs in the tumour microenvironment improves anti-tumour immunity in preclinical models. This may provide alternative therapies aiming at reducing immune suppression in the tumour.

Rao D ，Verburg F ，Renner K ，Peeper DS ，Lacroix R ，Blank CU ... -  《-》

CD8(+) cytotoxic T lymphocytes in cancer immunotherapy: A review.

CD8+ cytotoxic T lymphocytes (CTLs) are preferred immune cells for targeting cancer. During cancer progression, CTLs encounter dysfunction and exhaustion due to immunerelated tolerance and immunosuppression within the tumor microenvironment (TME), with all favor adaptive immune-resistance. Cancer-associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and regulatory T cells (Tregs) could make immunologic barriers against CD8 + T cell-mediated antitumor immune responses. Thus, CD8 + T cells are needed to be primed and activated toward effector CTLs in a process called tumor immunity cycle for making durable and efficient antitumor immune responses. The CD8 + T cell priming is directed essentially as a corroboration work between cells of innate immunity including dendritic cells (DCs) and natural killer (NK) cells with CD4 + T cells in adoptive immunity. Upon activation, effector CTLs infiltrate to the core or invading site of the tumor (so-called infiltrated-inflamed [I-I] TME) and take essential roles for killing cancer cells. Exogenous reactivation and/or priming of CD8 + T cells can be possible using rational immunotherapy strategies. The increase of the ratio for costimulatory to coinhibitory mediators using immune checkpoint blockade (ICB) approach. Programmed death-1 receptor (PD-1)-ligand (PD-L1) and CTL-associated antigen 4 (CTLA-4) are checkpoint receptors that can be targeted for relieving exhaustion of CD8 + T cells and renewing their priming, respectively, and thereby eliminating antigen-expressing cancer cells. Due to a diverse relation between CTLs with Tregs, the Treg activity could be dampened for increasing the number and rescuing the functional potential of CTLs to induce immunosensitivity of cancer cells.

Farhood B ，Najafi M ，Mortezaee K 《-》