Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies

Abstract

With the broad application of cancer immunotherapies such as immune checkpoint inhibitors in multiple cancer types, the immunological landscape in the tumor microenvironment (TME) has become enormously important for determining the optimal cancer treatment. Tumors can be immunologically divided into two categories: inflamed and non-inflamed based on the extent of immune cell infiltration and their activation status. In general, immunotherapies are preferable for the inflamed tumors than for non-inflamed tumors. Regulatory T cells (Tregs), an immunosuppressive subset of CD4+ T cells, play an essential role in maintaining self-tolerance and immunological homeostasis. In tumor immunity, Tregs compromise immune surveillance against cancer in healthy individuals and impair the antitumor immune response in tumor-bearing hosts. Tregs, therefore, accelerate immune evasion by tumor cells, leading to tumor development and progression in various types of cancer. Therefore, Tregs are considered to be a crucial therapeutic target for cancer immunotherapy. Abundant Tregs are observed in the TME in many types of cancer, both in inflamed and non-inflamed tumors. Diverse mechanisms of Treg accumulation, activation, and survival in the TME have been uncovered for different tumor types, indicating the importance of understanding the mechanism of Treg infiltration in each patient when selecting the optimal Treg-targeted therapy. Here, we review recent advances in the understanding of mechanisms leading to Treg abundance in the TME to optimize Treg-targeted therapy. Furthermore, in addition to the conventional strategies targeting cell surface molecules predominantly expressed by Tregs, reagents targeting molecules and signaling pathways specifically employed by Tregs for infiltration, activation, and survival in each tumor type are illustrated as novel Treg-targeted therapies. The effectiveness of immune precision therapy depends on conditions in the TME of each cancer patient.

Black raspberry extract inhibits regulatory T-cell activity in a murine model of head and neck squamous cell carcinoma chemoprevention

“…Our results demonstrate that dietary BRB-E significantly inhibits CD4 + FoxP3 + Treg accumulation within the primary tumors of the oral cavity, as evidenced by a reduction in Treg numbers as well as by decreased mRNA transcripts in the tongue for Foxp3 and Ctla4 , markers indicative of Treg recruitment and activity ( 18 ). Mechanisms that mediate this reduced recruitment of Tregs to HNSCC tumor microenvironments following BRB-E administration are still under active investigation, although chemokine-dependent infiltration via Ccl1, Ccl18, and Ccl22, and Vegfa-dependent recruitment are potential mechanisms ( 41 ). Indeed, BRB has been shown to inhibit angiogenesis in oral and esophageal cancers ( 42 , 43 ).…”

Development and Validation of a Pyroptosis-Related Signature for Predicting Prognosis in Hepatocellular Carcinoma

“…Besides, increasing studies observed that tumor-associated macrophages were associated with tumor-promoting inflammation and may favor tumor initiation and progression ( Mantovani et al, 2017 ; Ngambenjawong et al, 2017 ). Meanwhile, high-level intratumoral Tregs designed a generalized immunosuppressive tumor microenvironment and protected tumor cells from the host’s immune surveillance ( Nishikawa and Koyama, 2021 ). Previous study proposed that the presence of B cells in tumors was associated with a better prognosis for patients receiving immunotherapy, and they speculate that B cells may support CD8+T cells to effectively fight tumor cells ( Cabrita et al, 2020 ; Petitprez et al, 2020 ).…”

LncRNAs Target Ferroptosis-Related Genes and Impair Activation of CD4+ T Cell in Gastric Cancer

“…It has been reported that the infiltration of cytotoxic T cells and memory T cells was associated with good prognosis in gastric patients ( Chang et al, 2014 ). Although the current tumor immunotherapy targets mainly focus on CD8 + T cells, the role of conventional CD4 + T cells in tumor immunity has gradually attracted attention ( Nishikawa and Koyama, 2021 ). CD4 + effector T cells can enhance immunity by regulating dendritic cells or stimulating other proinflammatory cells of the myeloid lineage ( Behrens et al, 2004 ).…”