4.6 Review

Therapeutic targeting of regulatory T cells in cancer

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Summary: This study investigates the potential of Ivuxolimab in the treatment of cancer. The results demonstrate that Ivuxolimab is well tolerated and safe, and shows anti-tumor activity. Additionally, this study also finds that Ivuxolimab can activate the immune system, enhancing T-cell activation and proliferation, and has a certain control effect on tumors.

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Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs

Simon Eschweiler et al.

Summary: This study assessed the effects of PI3K delta inhibitors in patients with head and neck cancer, finding that it reduced the number of regulatory T cells in tumors and enhanced the cytotoxic potential of tumor-infiltrating T cells. However, high doses of the inhibitors led to immune-related adverse events, indicating the need for alternative dosing regimens to limit toxicity.

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CD30+OX40+ Treg is associated with improved overall survival in colorectal cancer

Jian Hang Lam et al.

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Metabolic support of tumour-infiltrating regulatory T cells by lactic acid

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Summary: T-reg cells exhibit broad heterogeneity in glucose metabolism within normal and transformed tissues, utilizing an alternative metabolic pathway to maintain their suppressive function and proliferation. Glucose uptake is correlated with poorer suppressive function and long-term instability, while high-glucose conditions impair T-reg cell function and stability. Additionally, T-reg cells upregulate pathways involved in the metabolism of lactic acid, with lactate uptake being dispensable for peripheral T-reg cells but required intratumorally for slowed tumor growth and increased response to immunotherapy.

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Prevalence of intratumoral regulatory T cells expressing neuropilin-1 is associated with poorer outcomes in patients with cancer

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Summary: Despite the success of immune checkpoint blockade therapy, targeting regulatory T cells (T-regs) within the tumor microenvironment remains a challenge due to the need for specificity to avoid systemic inflammation. Neuropilin-1 (NRP1) is preferentially expressed by intratumoral T-regs and may indicate higher disease burden in patients. NRP1 marks a transient activation state of human T-regs driven by continuous T cell receptor signaling and interleukin-2 exposure.

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Regulatory T cells promote cancer immune-escape through integrin αvβ8-mediated TGF-β activation

Alexandra Laine et al.

Summary: The presence of TGF beta in the tumor microenvironment is a significant cancer immune-escape mechanism. This study shows that regulatory T cells work in concert with cancer cells to produce bioactive TGF beta, creating an immunosuppressive micro-environment. The activation of TGF beta by Treg cells through the expression of avb8 integrin’s b8 chain is necessary for tumor growth.

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Therapeutic depletion of CCR8+ tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy

Helena Van Damme et al.

Summary: Regulatory T cells (Tregs) play a role in antitumor immunotherapy, but lack of selectivity for tumor-infiltrating Tregs can lead to adverse effects. CCR8-specific nanobodies were developed to selectively deplete tumor-promoting Tregs in mouse and human tumors, synergizing with anti-PD-1 therapy and reducing tumor growth through NK cell-dependent mechanisms. Targeting CCR8 may be an effective and safe strategy for antitumor immunotherapy.

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Fc-Optimized Anti-CCR8 Antibody Depletes Regulatory T Cells in Human Tumor Models

Joseph R. Campbell et al.

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CCR8 marks highly suppressive Treg cells within tumours but is dispensable for their accumulation and suppressive function

Sarah K. Whiteside et al.

Summary: CCR8 function is not essential for Treg cell accumulation and immunosuppressive function within tumors, suggesting that depletion of CCR8(+) Treg cells rather than blockade of CCR8 function may be a more promising avenue for selective immunotherapy.

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TIGIT and PD1 Co-blockade Restores ex vivo Functions of Human Tumor-Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

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CD39 Regulation and Functions in T Cells

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Regulatory T cells express Tumor Necrosis Factor Receptor 2 with the highest intensity among CD4+ T cells in the draining lymph nodes of breast cancer

Atri Ghods et al.

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First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas

Sarina A. Piha-Paul et al.

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