Venetoclax Induces BCL-2-Dependent Treg to TH17 Plasticity to Enhance the Antitumor Efficacy of Anti-PD-1 Checkpoint Blockade.

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Rosy Liao, Jocelyn Y Hsu, Nada S Aboelella, Joshua A McKeever, Anika T Thomas-Toth, Andrew S Koh, James L LaBelle
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Abstract

The specific BCL-2 small molecule inhibitor venetoclax induces apoptosis in a wide range of malignancies, which has led to rapid clinical expansion in its use alone and in combination with chemotherapy and immune-based therapies against a myriad of cancer types. While lymphocytes, and T cells in particular, rely heavily on BCL-2 for survival and function, the effects of small molecule blockade of the BCL-2 family on surviving immune cells is not fully understood. We aimed to better understand the effect of systemic treatment with venetoclax on regulatory T cells (Treg), which are relatively resistant to cell death induced by specific drugging of BCL-2 compared to other T cells. We found that BCL-2 blockade altered Treg transcriptional profiles and mediated Treg plasticity toward a TH17-like Treg phenotype, resulting in increased IL17A production in lymphoid organs and within the tumor microenvironment. Aligned with previously described augmented antitumor effects observed when combining venetoclax with anti-PD-1 checkpoint inhibition, we also demonstrated that Treg-specific genetic BCL-2 knockout combined with anti-PD-1 induced tumor regression and conferred overlapping genetic changes with venetoclax-treated Tregs. As long-term combination therapies using venetoclax gain more traction in the clinic, an improved understanding of the immune-modulatory effects caused by venetoclax may allow expansion of its use against malignancies and immune-related diseases.

Venetoclax诱导BCL-2依赖性Treg到TH17的可塑性,从而增强抗PD-1检查点阻断的抗肿瘤疗效。
特异性 BCL-2 小分子抑制剂 Venetoclax 可诱导多种恶性肿瘤细胞凋亡,因此其单独使用或与化疗和免疫疗法联合使用以治疗多种癌症的临床应用迅速扩大。虽然淋巴细胞,尤其是 T 细胞的存活和功能在很大程度上依赖于 BCL-2,但小分子阻断 BCL-2 家族对存活的免疫细胞的影响还不完全清楚。与其他T细胞相比,调节性T(Treg)细胞对BCL-2特异性药物诱导的细胞死亡具有相对抵抗力。我们发现,BCL-2阻断改变了Treg的转录谱,并介导Treg向TH17样Treg表型的可塑性发展,导致淋巴器官和肿瘤微环境中IL-17A的产生增加。与之前描述的将 venetoclax 与抗-PD-1 检查点抑制相结合可增强抗肿瘤效果的观点一致,我们还证明,Treg 特异性基因 BCL-2 基因敲除与抗-PD-1 结合可诱导肿瘤消退,并与 venetoclax 处理过的 Treg 产生重叠的基因变化。随着使用venetoclax的长期联合疗法在临床上越来越受重视,对venetoclax引起的免疫调节效应的进一步了解可能会扩大其在恶性肿瘤和免疫相关疾病中的应用。
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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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