Quimica biologica, IQUIBICEN-CONICET-UBA, Ciudad Autonoma de Buenos Aires, Argentina.
U981, INSERM, Paris, Île-de-France, France.
J Immunother Cancer. 2020 Dec;8(2). doi: 10.1136/jitc-2020-001535.
Prostate cancer (PCa) is a major health problem worldwide. Taxol derivatives-based chemotherapies or immunotherapies are usually proposed depending on the symptomatic status of the patient. In the case of immunotherapy, tumors develop robust immune escape mechanisms that abolish any protective response, and to date why prostate cancer is one of the most resistant diseases remains unresolved.
By using a combination of clinical data to study the transcriptome of metastasis samples from patients with castration-refractory prostate cancer, and state of the art cellular and molecular biology assays in samples from tumor-bearing mice that have been submitted to surgical resection of the tumor before receiving a vaccination, we answered several essential questions in the field of immunotherapy for prostate cancer. We also used two different methods to inhibit the expression of galectin-3 (Gal-3) in tumor cells: a stable RNA interference method to control the expression of this galectin efficiently only in tumor cells, and low and non-cytotoxic doses of docetaxel to easily transfer our findings to clinical settings.
Herein, we show for the first time that Gal-3 expressed by prostate tumor cells is the main immune checkpoint responsible for the failure of vaccine-based immunotherapy. Our results show that low and non-cytotoxic doses of docetaxel lead to the inhibition of Gal-3 expression in PCa cells as well as in clinical samples of patients with metastatic and castration-resistant PCa promoting a Th1 response. We thus optimized a prostate cancer animal model that undergoes surgical resection of the tumor to mimic prostatectomy usually performed in patients. Importantly, using Gal-3-knocked down-PCa cells or low and non-cytotoxic doses of taxane before vaccination, we were able to highly control tumor recurrence through a direct impact on the proliferation and infiltration of CD8+ cytotoxic T.
Thus, Gal-3 expression by PCa cells is a crucial inhibitor for the success of immunotherapy, and low doses of docetaxel with non-cytotoxic effect on leukocyte survival could be used before immunotherapy for all patients with PCa to reduce the expression of this critical negative immune checkpoint, pre-conditioning the tumor-microenvironment to activate an antitumor immune response and promote tumor-free outcome.
前列腺癌（PCa）是全球范围内的一个主要健康问题。根据患者的症状状况，通常会提出紫杉醇衍生物为基础的化疗或免疫疗法。在免疫疗法的情况下，肿瘤会发展出强大的免疫逃逸机制，从而消除任何保护反应，迄今为止，为什么前列腺癌是最具抵抗力的疾病之一仍未得到解决。
通过使用临床数据组合来研究去势抵抗性前列腺癌患者转移样本的转录组，并在接受肿瘤切除手术之前接受疫苗接种的荷瘤小鼠样本中使用最先进的细胞和分子生物学检测方法，我们回答了前列腺癌免疫治疗领域的几个基本问题。我们还使用了两种不同的方法来抑制肿瘤细胞中半乳糖凝集素-3（Gal-3）的表达：一种稳定的 RNA 干扰方法可有效控制仅在肿瘤细胞中表达这种半乳糖凝集素，以及低剂量和非细胞毒性的多西紫杉醇，以轻松将我们的发现转化为临床环境。
本文首次表明，前列腺肿瘤细胞表达的 Gal-3 是导致基于疫苗的免疫治疗失败的主要免疫检查点。我们的结果表明，低剂量和非细胞毒性的多西紫杉醇会导致 PCa 细胞以及转移性和去势抵抗性 PCa 患者的临床样本中 Gal-3 表达的抑制，从而促进 Th1 反应。因此，我们优化了一种前列腺癌动物模型，该模型对肿瘤进行手术切除，以模拟通常在患者中进行的前列腺切除术。重要的是，使用 Gal-3 敲低的 PCa 细胞或在接种疫苗之前使用低剂量和非细胞毒性的紫杉烷，可以通过直接影响 CD8+细胞毒性 T 的增殖和浸润来高度控制肿瘤复发。
因此，PCa 细胞的 Gal-3 表达是免疫治疗成功的关键抑制剂，低剂量的多西紫杉醇对白细胞存活没有细胞毒性作用，可用于所有 PCa 患者的免疫治疗之前，以降低这种关键负免疫检查点的表达，预先调节肿瘤微环境以激活抗肿瘤免疫反应并促进无肿瘤结局。
