Department of Oncology, Laboratory of Gynecological Oncology, University of Leuven, Leuven, Belgium.
Department of Human Genetics, Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium.
Clin Transl Med. 2024 May;14(5):e1655. doi: 10.1002/ctm2.1655.
Uterine leiomyosarcomas (uLMS) are aggressive tumours with poor prognosis and limited treatment options. Although immune checkpoint blockade (ICB) has proven effective in some 'challenging-to-treat' cancers, clinical trials showed that uLMS do not respond to ICB. Emerging evidence suggests that aberrant PI3K/mTOR signalling can drive resistance to ICB. We therefore explored the relevance of the PI3K/mTOR pathway for ICB treatment in uLMS and explored pharmacological inhibition of this pathway to sensitise these tumours to ICB.
We performed an integrated multiomics analysis based on TCGA data to explore the correlation between PI3K/mTOR dysregulation and immune infiltration in 101 LMS. We assessed response to PI3K/mTOR inhibitors in immunodeficient and humanized uLMS patient-derived xenografts (PDXs) by evaluating tumour microenvironment modulation using multiplex immunofluorescence. We explored response to single-agent and a combination of PI3K/mTOR inhibitors with PD-1 blockade in humanized uLMS PDXs. We mapped intratumoural dynamics using single-cell RNA/TCR sequencing of serially collected biopsies.
PI3K/mTOR over-activation (pS6) associated with lymphocyte depletion and wound healing immune landscapes in (u)LMS, suggesting it contributes to immune evasion. In contrast, PI3K/mTOR inhibition induced profound tumour microenvironment remodelling in an ICB-resistant humanized uLMS PDX model, fostering adaptive anti-tumour immune responses. Indeed, PI3K/mTOR inhibition induced macrophage repolarisation towards an anti-tumourigenic phenotype and increased antigen presentation on dendritic and tumour cells, but also promoted infiltration of PD-1+ T cells displaying an exhausted phenotype. When combined with anti-PD-1, PI3K/mTOR inhibition led to partial or complete tumour responses, whereas no response to single-agent anti-PD-1 was observed. Combination therapy reinvigorated exhausted T cells and induced clonal hyper-expansion of a cytotoxic CD8+ T-cell population supported by a CD4+ T1 niche.
Our findings indicate that aberrant PI3K/mTOR pathway activation contributes to immune escape in uLMS and provides a rationale for combining PI3K/mTOR inhibition with ICB for the treatment of this patient population.
子宫平滑肌肉瘤（uLMS）是一种侵袭性强、预后差、治疗选择有限的肿瘤。尽管免疫检查点阻断（ICB）已被证明对一些“具有挑战性的治疗”癌症有效，但临床试验表明 uLMS 对 ICB 无反应。新出现的证据表明，异常的 PI3K/mTOR 信号通路可导致对 ICB 的耐药。因此，我们探索了 PI3K/mTOR 通路对 uLMS 中 ICB 治疗的相关性，并探索了通过抑制该通路使这些肿瘤对 ICB 敏感的可能性。
我们基于 TCGA 数据进行了综合多组学分析，以探索 101 例 LMS 中 PI3K/mTOR 失调与免疫浸润之间的相关性。我们通过评估多聚免疫荧光分析肿瘤微环境的调节，来评估免疫缺陷和人源化 uLMS 患者来源异种移植瘤（PDX）中 PI3K/mTOR 抑制剂的反应。我们在人源化 uLMS PDX 中探索了单药和 PI3K/mTOR 抑制剂联合 PD-1 阻断的反应。我们使用单细胞 RNA/TCR 测序对连续收集的活检进行了肿瘤内动态分析。
PI3K/mTOR 过度激活（pS6）与（u）LMS 中的淋巴细胞耗竭和伤口愈合免疫景观相关，提示其有助于免疫逃逸。相比之下，PI3K/mTOR 抑制在 ICB 耐药的人源化 uLMS PDX 模型中诱导了肿瘤微环境的深刻重塑，促进了适应性抗肿瘤免疫反应。事实上，PI3K/mTOR 抑制诱导了巨噬细胞向抗肿瘤表型的极化，并增加了树突状细胞和肿瘤细胞上的抗原呈递，但也促进了 PD-1+T 细胞的浸润，这些 T 细胞表现出衰竭表型。当与抗 PD-1 联合使用时，PI3K/mTOR 抑制导致部分或完全肿瘤反应，而单药抗 PD-1 则没有反应。联合治疗使衰竭的 T 细胞恢复活力，并诱导支持 CD4+T1 龛的细胞毒性 CD8+T 细胞群的克隆超扩增。
我们的研究结果表明，异常的 PI3K/mTOR 通路激活导致 uLMS 中的免疫逃逸，并为联合 PI3K/mTOR 抑制与 ICB 治疗这一患者群体提供了依据。
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