PGE2-EP2/EP4 axis: A new perspective on cancer immunotherapy

Abstract

Lacher et al.¹ in a recent publication in Nature, revealed a crucial mechanism that limits the responsiveness of TCF1⁺ tumor-infiltrating lymphocytes (TILs) to interleukin-2 (IL-2), thereby impeding the anti-cancer T cell response derived from these cells. They identified the prostaglandin E₂ (PGE₂)-EP₂/EP₄ axis as a molecular target to restore IL-2 responsiveness in anti-cancer TILs, leading to cancer immune control. This study provides critical insights into the molecular interactions that govern TIL functionality and IL-2 responsiveness, which are essential for effective immunotherapy. Moreover, it suggests that therapeutic strategies aimed at inhibiting the PGE₂-EP₂/EP₄ axis could enhance the efficacy of IL-2 based immunotherapies, potentially offering a new avenue for cancer treatment, particularly in tumors where TILs are a significant component of the immune response (Figure 1).

Tumor immunotherapy marks a significant breakthrough in cancer treatment, with research into immune cells and the tumor microenvironment (TME) uncovering various regulatory factors that influence immune cell activity within tumors. Tumor-derived PGE₂ plays a crucial role in tumor immune evasion and acts as a key inflammatory mediator. Previous studies have shown that PGE₂ affects immune cell activity, function, and metabolism, impacting their ability to recognize and target tumors.^2-4 This regulatory role of PGE₂ is particularly important for the efficacy of tumor immunotherapy, especially concerning CD8⁺ T cells. CD8⁺ T cells are vital components of the immune system, responsible for identifying and eliminating tumor cells by recognizing specific antigens on their surfaces. Upon recognition, they release perforins and granzymes to induce apoptosis in tumor cells, contributing to tumor clearance and the success of immunotherapy.⁵ However, the mechanisms by which PGE₂ limits the effector expansion of CD8⁺ T cells, particularly in the TME, remain unclear. This study investigates the interaction between PGE₂ and CD8⁺ T cells, revealing how PGE₂ restricts the effector expansion of tumor-infiltrating stem-like CD8⁺ T cells and its significance in tumor immunotherapy. The findings provide a theoretical basis and clinical guidance for optimizing immunotherapy strategies.

This study has revealed that tumor-derived PGE₂ significantly inhibits the expansion and effector differentiation of TCF1⁺ CD8⁺ TILs, which are crucial for sustaining a long-term anti-tumor response. The expansion of these T cells ensures a sufficient quantity of effector cells, while their differentiation into effector cells is essential for directly attacking and eliminating tumor cells. Therefore, the inhibition of these processes by PGE₂ severely impairs the ability of the immune system to effectively target and eradicate tumor cells. PGE₂, through the EP₂/EP₄ signaling pathway, suppresses TILs’ responsiveness to IL-2. Specifically, EP₂/EP₄ deficiency in TCF1⁺ TILs enhances the activity of transcription factors (TFs) like NFKB1, REL, JUN, and TBX21, which are crucial for effector differentiation. Additionally, PGE₂ stimulates cytokine signaling factors (CYFs) like STAT4 and IRF1, along with survival signals such as RUNX2 and TRP53. These changes ultimately impair TILs' anti-tumor effectiveness within the TME.

This study demonstrated the significance of the IL-2 receptor (IL-2R) signaling pathway in EP₂/EP₄-deficient TILs. Blocking the IL-2R signaling pathway eliminates the expansion advantage of EP₂/EP₄-deficient TILs within the tumor, reducing their effector differentiation capability. This finding highlights the critical role of the IL-2R signaling pathway in specific antigen CD8⁺ TILs under PGE₂-EP₂/EP₄ deficiency, offering potential therapeutic strategies. PGE₂ has been identified as a significant modulator of this pathway, promoting immunosuppression and facilitating tumor progression. Therefore, a comprehensive understanding of the IL-2 signaling pathway's role in this process is vital. Recent studies have shown that IL-2 can enhance the proliferation and activation of CD8⁺ T cells, which are critical for antitumor immunity. However, in the presence of PGE₂, this pathway is often subverted, leading to reduced T cell efficacy and contributing to an immunosuppressive TME. By targeting the IL-2 signaling pathway, particularly in the context of PGE₂-EP₂/EP₄ deficiency, it may be possible to restore effective T cell responses and improve therapeutic outcomes.

Deficient EP₂/EP₄ signaling in specific antigen CD8⁺ T cells shows a strong anti-tumor response, leading to complete tumor eradication. These cells demonstrate substantial anti-tumor effects in models, reinforcing their crucial role in tumor immunity. EP₂/EP₄-deficient T cells also exhibit strong immune protective effects in diverse tumor models, such as MC38-OVA and D4M.3A-pOVA. This supports the intervention in the PGE₂-EP₂/EP₄ signaling pathway to promote the expansion and differentiation of specific CD8⁺ T cells in tumors.

The study revealed the critical role of antigen-specific TILs in eradicating tumors. T cells lacking EP₂/EP₄ showed continued expansion and specialized differentiation within tumors. This further confirms the significant role of these T cells within tumors. By intervening in the IL-2R signaling pathway to block IL-2R signal transduction, the advantage of EP₂/EP₄-deficient T cells in tumor expansion was eliminated, emphasizing the significance of this signaling pathway in anti-tumor immunity.

In-depth research into PGE₂'s role in regulating tumor-infiltrating CD8⁺ T cells has yielded critical insights. This study highlights the pivotal role of tumor-derived PGE₂ in the TME, particularly in restraining CD8⁺ TIL expansion and the effector differentiation of TCF1⁺ stem-like TILs, offering new perspectives on cancer immune evasion mechanisms. Previous studies have shown that PGE₂ inhibits TIL responses to IL-2 via EP₂/EP₄ pathways, emphasizing their role in modulating immune responses. This study advances understanding by revealing EP₂/EP₄ signaling's fine-tuning role in TCF1⁺ TILs, shedding light on tumor immune evasion. It uniquely underscores how PGE₂-mediated EP₂/EP₄ signaling modulates IL-2 transduction, contributing to tumor-immune interactions and potential therapeutic targets. Specifically, PGE₂ inhibits TILs’ IL-2 responsiveness by downregulating IL-2 receptor subunits, particularly IL-2Rβ and γc chains. The study proposes an innovative strategy to enhance CD8⁺ T cells’ IL-2 responsiveness by disrupting PGE₂-EP₂/EP₄ signaling, thereby inducing protective TIL-mediated anti-cancer immunity, with clinical relevance in immunotherapy.

Future research should focus on further elucidating the role of the PGE₂-EP₂/EP₄ signaling axis in tumor immunity, particularly its regulatory effects on other key immune cells such as CD4⁺ T cells and macrophages. Understanding these mechanisms could provide new insights into how modulation of this axis might enhance T cell-mediated cytotoxicity against tumor cells, thereby offering novel strategies to improve cancer immunotherapy. Additionally, the complexities of IL-2 signaling remain incompletely understood, warranting future studies to identify other potential regulatory factors and their interactions within this pathway, which could uncover new therapeutic targets. Furthermore, significant gaps remain in the investigation of the feasibility and safety of targeting the PGE₂-EP₂/EP₄ axis in clinical settings. Future preclinical and clinical studies should prioritize the evaluation of these targets’ safety and efficacy to lay the groundwork for their clinical application. Addressing these issues will not only deepen our understanding of tumor immune evasion mechanisms but also support the development of next-generation immunotherapies, ultimately improving survival rates and quality of life for cancer patients.

Lin Chen and Jian-Liang Zhou: Conceived the structure of the manuscript and revised the manuscript. Lin Chen: Drafted the initial manuscript. Yu-Xin Xu: Made the figure. All authors read and approved the final manuscript.

The authors declare no conflict of interest.

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