Nature Communications | αTIGIT-IL2 achieves tumor regression by inducing fragility in tumor-infiltrating regulatory T cells

This study designed a novel immune cytokine αTIGIT-IL2 that effectively reconstructs the anti-tumor immune microenvironment by specifically targeting regulatory T cells (Treg cells) and inducing their fragility. This approach demonstrated remarkable anti-tumor efficacy in mouse models, particularly when combined with PD-1 blockade, offering a new therapeutic strategy for triple-negative breast cancer.

 

Literature Overview
The article, 'αTIGIT-IL2 achieves tumor regression by inducing fragility in tumor-infiltrating regulatory T cells,' published in the journal Nature Communications, reviews and summarizes the key role of regulatory T cells (Treg cells) in the tumor immune microenvironment and how the fusion of IL-2 with anti-TIGIT antibodies can specifically target Treg cells and reduce their immunosuppressive functions. The study further explores the anti-tumor capabilities of this immune cytokine in various mouse tumor models, particularly showing significant efficacy in triple-negative breast cancer models resistant to immune checkpoint blockade therapies.

Background Knowledge
Regulatory T cells (Treg cells) play a crucial role in maintaining immune tolerance and suppressing excessive immune responses. However, in the context of tumor immunotherapy, their high expression of CD25 and TIGIT receptors can limit anti-tumor immune responses. IL-2 is a key cytokine in regulating T cell proliferation and activation; however, high-dose IL-2 may cause systemic toxicity, while low-dose IL-2 can promote Treg cell proliferation, thereby weakening anti-tumor immunity. Therefore, targeting Treg cells to reduce their immunosuppressive function is critical for improving the effectiveness of immunotherapy. TIGIT, as a novel immune checkpoint molecule, is highly expressed on tumor-infiltrating T cells, particularly on Treg cells, and is closely associated with T cell functional exhaustion. This study constructs the αTIGIT-IL2 immune cytokine to specifically target Treg cells, inducing their transformation into a fragile phenotype, thereby triggering a pro-inflammatory tumor microenvironment and enhancing anti-tumor immunity. This study provides theoretical and experimental support for the development of next-generation immune cytokines targeting Treg cells.

 

 

Research Methods and Experiments
Researchers fused IL-2 with the single-chain variable fragment (scFv) of an anti-TIGIT monoclonal antibody (13G6) and linked it to the human IgG1 Fc region to construct the αTIGIT-IL2 immune cytokine. Its anti-tumor efficacy was evaluated using multiple mouse tumor models, including MC38, B16F10, and EO771 models. Various techniques, such as flow cytometry, scRNA-seq, immunohistochemistry, and loss-of-function experiments, were employed to analyze the phenotypic changes of Treg cells, functional reprogramming of neutrophils, and enhanced CD8+ T cell function.

Key Conclusions and Perspectives

• αTIGIT-IL2 specifically targets Treg cells within the tumor microenvironment, reduces their immunosuppressive functions, and induces them to produce IFN-γ, thereby promoting a pro-inflammatory tumor microenvironment.
• The pro-inflammatory microenvironment facilitates the recruitment and functional reprogramming of neutrophils, enhances MHC-II expression, and thereby improves CD8+ T cell interaction, augmenting anti-tumor immune responses.
• Combining αTIGIT-IL2 with PD-1 blockade completely eliminated tumors in triple-negative breast cancer mouse models, demonstrating a synergistic effect.
• This study reveals the central role of Treg cells in tumor immunity and proposes a novel strategy to enhance anti-tumor immune responses by targeting Treg cells and inducing their fragility.

Research Significance and Prospects
This study presents an innovative immune cytokine design strategy that effectively breaks immune tolerance and enhances anti-tumor immune responses by targeting Treg cells and inducing their functional fragility. Future work may focus on further optimizing this molecule to reduce systemic toxicity and exploring its application in other tumor models to facilitate clinical translation.

 

 

Conclusion
αTIGIT-IL2 is a novel immune cytokine that fuses anti-TIGIT antibodies with IL-2. It induces fragility in tumor-infiltrating regulatory T cells, thereby reducing their immunosuppressive function and promoting the formation of a pro-inflammatory microenvironment. This microenvironment activates neutrophils and CD8+ T cells, enhancing anti-tumor immune responses. The study also demonstrates that αTIGIT-IL2, when combined with PD-1 blockade, effectively eliminates triple-negative breast cancer resistant to immune checkpoint therapy, offering a new targeted strategy for cancer immunotherapy. This research lays the theoretical foundation for the development of next-generation immune cytokines and provides important insights for future clinical translation.

 

Tianci Wang, Yupu Xu, Zhengfeng Zhang, Zhigang Tian, and Xiaohu Zheng. αTIGIT-IL2 achieves tumor regression by promoting tumor-infiltrating regulatory T cell fragility in mouse models. Nature Communications.