CXCL13通过调控肿瘤免疫微环境诱导抗肿瘤免疫的机制研究

Tumor immune microenvironment plays a central role in tumorigenesis and tumor progression. Immunotherapy targeting tumor immune microenvironment shows good clinical application. Chemokines are important regulators of tumor immune microenvironment. CXC chemokine ligand-13 (CXCL13) is expression in breast cancer and a series of other tumors. However, the influence of intratumorally expression CXCL13 on tumor progression is still in debate. Previously, our group constructed a stable stain of mouse 4T1 breast cancer which highly expressed CXCL13. When inoculated in the mouse, the stable stain grew slowly and gradually regressed. Tumor tissue detection showed increase of tumor infiltrating lymphocytes, especially upregulation of CD4+ and CD8+ T lymphocytes. Rechallenge of tumor regression mice with parental 4T1 showed decreased tumor formation rate and slow growth. The researches abroad and ours all indicate that CXCL13 expression in tumor microenvironment recruit immune cells and mediate specific anti-tumor immunity. Based on previous investigation, in this item, we aim to prove that the intratumorally expressed CXCL13 elicits specific anti-tumor immunity, and study the possible immune effect from the aspect of humoral immunity and cellular immunity, focusing on the immune cells in tumor microenvironment and immunologic mechanism. The execution of this item is helpful for the clarification of the immune effect of intratumoral CXCL13 on tumor progression, and at the same time, providing new avenue for tumor immune therapy.

肿瘤免疫微环境在肿瘤发生发展中扮演重要角色，靶向调控肿瘤免疫微环境的免疫治疗具有很好的临床应用前景。趋化因子是肿瘤免疫微环境的重要调控因素。CXC趋化因子配体13（CXCL13）在乳腺癌等多种肿瘤中表达，但作用尚无定论。本课题组前期构建了CXCL13高表达的小鼠4T1乳腺癌稳定株，稳定株接种小鼠后生长缓慢并出现肿瘤消退，肿瘤中淋巴细胞浸润增加，其中CD4+和CD8+T细胞显著上调，肿瘤消退小鼠接种亲本4T1后成瘤率下降并且生长缓慢。我们和国外的研究均提示肿瘤微环境中的CXCL13可能募集了免疫细胞并介导了特异的抗肿瘤免疫。本项目拟在前期研究基础上证实CXCL13在肿瘤中的表达诱导了特异的抗肿瘤免疫，并从体液免疫和细胞免疫的角度研究免疫效应，重点探讨对肿瘤微环境中免疫细胞的影响和免疫机制。本项目的实施有助于阐明肿瘤微环境中的CXCL13在肿瘤进展中的免疫作用，并为肿瘤免疫治疗提供新的思路。

肿瘤免疫微环境在肿瘤发生发展中扮演重要角色，趋化因子是其重要调控因子。CXC趋化因子配体13（CXCL13）表达于乳腺癌等多种肿瘤，但与肿瘤发生发展、治疗反应及预后的关系尚不明确。我们前期研究发现CXCL13在乳腺癌肿瘤微环境的表达能介导肿瘤体内生长抑制，肿瘤完全消退小鼠再次接种亲本肿瘤后成瘤率降低，生长减慢。我们推测CXCL13可能诱导了特异的抗肿瘤免疫，目前尚无相关研究报道。本项目围绕“CXCL13在肿瘤细胞表达调控免疫微环境，促进抗肿瘤免疫的免疫机制”问题，证实了CXCL13在肿瘤微环境的表达能够介导特异的抗肿瘤免疫反应；完成体液免疫和细胞免疫检测；根据体液免疫和细胞免疫检测结果，对特定免疫细胞进行了中和抗体阻断，找到关键效应细胞群；完成CXCL13介导的肿瘤微环境浸润免疫细胞动态变化和原位检测；完成机体免疫细胞群的动态变化检测；从肿瘤疫苗角度对CXCL13用于肿瘤治疗进行初步探讨。综合前期工作和本项目结果，我们的研究证实：CXCL13在乳腺癌肿瘤微环境的高表达能显著抑制肿瘤体内生长与转移，其介导的肿瘤抑制与机体免疫有关且具有长期免疫记忆。CXCL13介导的抗肿瘤作用主要通过正向调控肿瘤局部免疫微环境，促进CD8+T细胞功能，抑制MDSC从而发挥抗肿瘤作用。我们的研究提示：CXCL13在乳腺癌肿瘤组织中的表达发挥了积极的抗肿瘤作用，为乳腺癌靶向肿瘤微环境的免疫治疗提供了新的策略。