Intermittent MEK Inhibition with GITR Costimulation Rescues T-cell Function for Increased Efficacy with CTLA-4 Blockade in Solid Tumor Models.

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Lauren Dong, Hyejin Choi, Sadna Budhu, Isabell Schulze, Svena Verma, Levi M Mangarin, Valeria Estrada Nevarro, Nezar Mehanna, Jonathan F Khan, Divya Venkatesh, Daniel Thach, Neal Rosen, Jedd D Wolchok, Taha Merghoub
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Abstract

MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression in tumor cells and improved T cell-mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T-cell receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and costimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor-draining lymph nodes and tumors and led to intratumoral regulatory T-cell destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses.

间歇性 MEK 抑制与 GITR 协同刺激可挽救 T 细胞功能,从而提高 CTLA-4 阻断剂在实体瘤模型中的疗效。
MEK 抑制剂(MEKis)在治疗依赖 MAPK/ERK 通路的癌症方面效果有限,原因是肿瘤细胞会采用各种抗药机制。CH5126766 (CKI27)是一种与MEK结合的抑制剂,它能阻止RAF的释放,减少其他MEK抑制剂常见的负反馈。我们观察到,CKI27 增加了肿瘤细胞上的 MHC 表达,提高了 T 细胞介导的杀伤力。然而,CKI27 也通过抑制 T 细胞受体信号传导下游激活的 MAPK/ERK 通路,降低了 T 细胞的增殖、活化和细胞溶解活性。因此,我们的目标是平衡 MEKis 的正负免疫调节作用,以实现与免疫疗法的最佳结合。间歇性给药 CKI27 可使 T 细胞部分恢复,而通过 GITR 和 OX-40 激动剂抗体进行联合刺激可完全缓解对 T 细胞功能的抑制。在 Kras 突变的肺癌和结肠癌小鼠模型中,间歇性服用 CKI27 和抗 GITR 能显著降低肿瘤生长,并延长存活时间,如果进一步结合 CTLA-4 免疫检查点阻断疗法。此外,这种三联疗法增加了肿瘤引流淋巴结和肿瘤中 CD8+ 和 CD4+ T 细胞的增殖、活化和效应/记忆亚群,并导致瘤内调节性 T 细胞(Treg)不稳定。这些数据将有助于在优化联合疗法时做出更明智的决定,克服耐药性、降低毒性并产生长期免疫反应。
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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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