小柯机器人

美国丹娜-法伯癌症研究所Jean J. Zhao等研究人员合作发现，PI3Kβ控制PTEN缺失的乳腺肿瘤的免疫逃避。该研究于2023年4月19日在线发表于国际一流学术期刊《自然》。

研究人员使用一种由Pten和Trp53（编码p53）缺失驱动的浸润性乳腺癌的合成基因工程小鼠模型，显示PI3Kβ的遗传失活导致了一种强大的抗肿瘤免疫反应，在合成免疫功能正常的小鼠中废除了肿瘤的生长，但在免疫缺陷的小鼠中没有。从机制上讲，在PTEN缺失的情况下，PI3Kβ的失活导致STAT3信号的减少和免疫刺激分子的表达增加，从而促进了抗肿瘤免疫反应。药理上的PI3Kβ抑制也引起了抗肿瘤免疫，并与免疫疗法协同抑制肿瘤的生长。对联合治疗有完全反应的小鼠显示出免疫记忆，并在再次挑战时阻断肿瘤。

这些研究结果证明了癌症中PTEN缺失和STAT3激活之间的分子机制，并表明PI3Kβ控制PTEN缺失肿瘤的免疫逃逸，为将PI3Kβ抑制剂与免疫疗法结合起来治疗PTEN缺失的乳腺癌提供了理论依据。

据介绍，PTEN肿瘤抑制因子的丧失是所有癌症类型中最常见的致癌因素之一。PTEN是PI3K信号的主要负调控因子。PI3Kβ亚型已被证明在PTEN缺失的肿瘤中发挥重要作用，但PI3Kβ活性的重要性的机制仍然难以确定。

附：英文原文

Title: PI3Kβ controls immune evasion in PTEN-deficient breast tumours

Author: Bergholz, Johann S., Wang, Qiwei, Wang, Qi, Ramseier, Michelle, Prakadan, Sanjay, Wang, Weihua, Fang, Rong, Kabraji, Sheheryar, Zhou, Qian, Gray, G. Kenneth, Abell-Hart, Kayley, Xie, Shaozhen, Guo, Xiaocan, Gu, Hao, Von, Thanh, Jiang, Tao, Tang, Shuang, Freeman, Gordon J., Kim, Hye-Jung, Shalek, Alex K., Roberts, Thomas M., Zhao, Jean J.

Issue&Volume: 2023-04-19

Abstract: Loss of the PTEN tumour suppressor is one of the most common oncogenic drivers across all cancer types1. PTEN is the major negative regulator of PI3K signalling. The PI3Kβ isoform has been shown to play an important role in PTEN-deficient tumours, but the mechanisms underlying the importance of PI3Kβ activity remain elusive. Here, using a syngeneic genetically engineered mouse model of invasive breast cancer driven by ablation of both Pten and Trp53 (which encodes p53), we show that genetic inactivation of PI3Kβ led to a robust anti-tumour immune response that abrogated tumour growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3Kβ inactivation in the PTEN-null setting led to reduced STAT3 signalling and increased the expression of immune stimulatory molecules, thereby promoting anti-tumour immune responses. Pharmacological PI3Kβ inhibition also elicited anti-tumour immunity and synergized with immunotherapy to inhibit tumour growth. Mice with complete responses to the combined treatment displayed immune memory and rejected tumours upon re-challenge. Our findings demonstrate a molecular mechanism linking PTEN loss and STAT3 activation in cancer and suggest that PI3Kβ controls immune escape in PTEN-null tumours, providing a rationale for combining PI3Kβ inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer.

DOI: 10.1038/s41586-023-05940-w

Source: https://www.nature.com/articles/s41586-023-05940-w

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