Immune checkpoint inhibitors in cancer therapy: a focus on T-regulatory cells.

Regulatory T cells (Tregs) play essential roles in immune homeostasis; however, their role in tumor microenvironment (TME) is not completely evident. Several studies reported that infiltration of Tregs into various tumor tissues promotes tumor progression by limiting antitumor immunity and supporting tumor immune evasion. Furthermore, in TME, Tregs include heterogeneous subsets of cells expressing different immunosuppressive molecules favoring tumor progression. For an effective cancer therapy, it is critical to understand the Treg heterogeneity and biology in the TME. Recent studies have shown that immune checkpoint molecules promote cancer progression through various antitumor inhibitory mechanisms. Recent advances in cancer immunotherapy have shown the promising potentials of immune checkpoint inhibitors (ICIs) in inducing antitumor immune responses and clinical benefits in patients with cancer at late stages. Most studies revealed the effect of ICIs on T effector cells, and little is known about their effect on Tregs. In this review, we highlight the effects of the ICIs, including anti-CTLA-4, anti-PD-1/PD-L1, anti-LAG-3, anti-TIM-3, and anti-TIGIT, on tumor-infiltrating and peripheral Tregs to elicit effector T-cell functions against tumors. Additionally, we discuss how ICIs may target Tregs for cancer immunotherapy.

Sasidharan Nair V ，Elkord E 《-》

Expression of costimulatory and inhibitory receptors in FoxP3(+) regulatory T cells within the tumor microenvironment: Implications for combination immunotherapy approaches.

The unprecedented success of immune checkpoint inhibitors has given rise to a rapidly growing number of immuno-oncology agents undergoing preclinical and clinical development and an exponential increase in possible combinations. Defining a clear rationale for combinations by identifying synergies between immunomodulatory pathways has therefore become a high priority. Immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment (TME) represent a major roadblock to endogenous and therapeutic tumor immunity. However, Tregs are also essential for the maintenance of immunological self-tolerance, and share many molecular pathways with conventional T cells including cytotoxic T cells, the primary mediators of tumor immunity. Hence the inability to specifically target and neutralize Tregs within the TME of cancer patients without globally compromising self-tolerance poses a significant challenge. Here we review recent advances in the characterization of tumor-infiltrating Tregs with a focus on costimulatory and inhibitory receptors. We discuss receptor expression patterns, their functional role in Treg biology and mechanistic insights gained from targeting these receptors in preclinical models to evaluate their potential as clinical targets. We further outline a framework of parameters that could be used to refine the assessment of Tregs in cancer patients and increase their value as predictive biomarkers. Finally, we propose modalities to integrate our increasing knowledge on Treg phenotype and function for the rational design of checkpoint inhibitor-based combination therapies. Such combinations have great potential for synergy, as they could concomitantly enhance cytotoxic T cells and inhibit Tregs within the TME, thereby increasing the efficacy of current cancer immunotherapies.

Toker A ，Ohashi PS 《-》

Treg-mediated acquired resistance to immune checkpoint inhibitors.

T Regulatory cells (Tregs) act as a double-edged sword by regulating immune homeostasis (protective role) and inhibiting immune responses in different disease settings (pathological role). They contribute to cancer development and progression by suppressing T effector cell (Teff) functions. Decreased ratios of intratumoral CD8+ T cells to Tregs have been associated with poor prognosis in most cancer types. Targeting immune checkpoints (ICs), such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1), by immune checkpoint inhibitors (ICIs) in cancer patients has been beneficial in inducing anti-tumor immune responses and improving clinical outcomes. However, response rates remain relatively low, ranging from 15 to 40% depending on cancer type. Additionally, a significant proportion of patients who initially demonstrates a clinical response can acquire resistance overtime. This acquired resistance could occur due to the emergence of compensatory mechanisms within the tumor microenvironment (TME) to evade the anti-tumor effects of ICIs. In this review, we describe the immunosuppressive role of Tregs in the TME, the effects of currently approved ICIs on Treg phenotype and function, and the mechanisms of acquired resistance to ICIs mediated by Tregs within the TME, such as the over-expression of ICs, the up-regulation of immunosuppressive molecules, and apoptotic Treg-induced immunosuppression. We also describe potential therapeutic strategies to target Tregs in combination with ICIs aiming to overcome such resistance and improve clinical outcomes. Elucidating the Treg-mediated acquired resistance mechanisms should benefit the designing of well-targeted therapeutic strategies to overcome resistance and maximize the therapeutic efficacy in cancer patients.

Saleh R ，Elkord E 《-》

Roles of regulatory T cells in cancer immunity.

CD4(+) regulatory T cells (Tregs) expressing the transcription factor FoxP3 are highly immune suppressive and play central roles in the maintenance of self-tolerance and immune homeostasis, yet in malignant tumors they promote tumor progression by suppressing effective antitumor immunity. Indeed, higher infiltration by Tregs is observed in tumor tissues, and their depletion augments antitumor immune responses in animal models. Additionally, increased numbers of Tregs and, in particular, decreased ratios of CD8(+) T cells to Tregs among tumor-infiltrating lymphocytes are correlated with poor prognosis in various types of human cancers. The recent success of cancer immunotherapy represented by immune checkpoint blockade has provided a new insight in cancer treatment, yet more than half of the treated patients did not experience clinical benefits. Identifying biomarkers that predict clinical responses and developing novel immunotherapies are therefore urgently required. Cancer patients whose tumors contain a large number of neoantigens stemming from gene mutations, which have not been previously recognized by the immune system, provoke strong antitumor T-cell responses associated with clinical responses following immune checkpoint blockade, depending on the resistance to Treg-mediated suppression. Thus, integration of a strategy restricting Treg-mediated immune suppression may expand the therapeutic spectrum of cancer immunotherapy towards patients with a lower number of neoantigens. In this review, we address the current understanding of Treg-mediated immune suppressive mechanisms in cancer, the involvement of Tregs in cancer immunotherapy, and strategies for effective and tolerable Treg-targeted therapy.

Takeuchi Y ，Nishikawa H 《-》

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

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.

Nishikawa H ，Koyama S 《Journal for ImmunoTherapy of Cancer》