CD81 通过阻断 CD274/PD-L1 的选择性自噬降解驱动放射抵抗性胶质母细胞瘤的免疫逃逸
CD81 drives immune evasion in radioresistant glioblastoma by blocking selective autophagic degradation of CD274/PD-L1.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题:The immune cell landscape of glioblastoma patients highlights a myeloid-enriched and immune suppressed microenvironment compared to metastatic brain tumors.
The immune cell landscape of glioblastoma patients highlights a myeloid-enriched and immune suppressed microenvironment compared to metastatic brain tumors.
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我们的结果明确了 BrM 和 GBM 免疫特征的主要特点,二者的区别在于免疫抑制性髓系细胞和缺乏效应功能的淋巴细胞水平不同。理解不同细胞在建立转移环境中的作用,对于提高新型靶向免疫治疗策略的疗效至关重要。
脑转移(BrM)常见于黑色素瘤、乳腺癌和肺癌患者,与不良临床预后相关。在此背景下,肿瘤微环境(TME)发挥重要作用,因为它要么促进要么抑制肿瘤进展。我们之前的研究已对胶质母细胞瘤(GBM)的免疫抑制微环境进行了表征。本研究旨在比较 BrM 和 GBM 的免疫特征,以识别可能在其差异化治疗中加以利用的潜在差异。
从20例BrM患者和19例GBM患者中采集了肿瘤和/或血液样本。采用多参数流式细胞术评估髓系和淋系细胞,以及TME和血液中免疫检查点的表达。在选定病例中,检测了分选髓系细胞的免疫抑制能力,并分析了髓系、淋系和肿瘤细胞群体的离体增殖。
髓系细胞的高频率在BrM和GBM中均占主导地位,但在GBM中观察到肿瘤相关巨噬细胞的存在更高,而BrM则以TIL(肿瘤浸润淋巴细胞)的显著存在为特征。耗竭标志物在原发性和转移性脑肿瘤的所有T细胞中均高表达。对单个BrM和GBM样本的细胞周期进行离体分析,揭示了增殖性肿瘤细胞和血液来源巨噬细胞的亚群,但静息的驻留小胶质细胞和少量增殖性淋巴细胞。从单个肺BrM中分选出的巨噬细胞表现出强烈的免疫抑制活性,与此前在原发GBM中显示的一致。最后,在GBM和BrM患者的血液中均观察到某些髓系细胞亚群的显著扩增。
Tumor and/or blood samples were taken from 20 BrM patients and 19 GBM patients. Multi-parametric flow cytometry was used to evaluate myeloid and lymphoid cells, as well as the expression of immune checkpoints in the TME and blood. In selected cases, the immunosuppressive ability of sorted myeloid cells was tested, and the ex vivo proliferation of myeloid, lymphoid and tumor cell populations was analyzed.
High frequencies of myeloid cells dominated both the BrM and GBM landscapes, but a higher presence of tumor-associated macrophages was observed in GBM, while BrM were characterized by a significant presence of tumor-infiltrating lymphocytes. Exhaustion markers were highly expressed in all T cells from both primary and metastatic brain tumors. Ex vivo analysis of the cell cycle of a single sample of a BrM and of a GBM revealed subsets of proliferating tumor cells and blood-derived macrophages, but quiescent resident microglial cells and few proliferating lymphocytes. Macrophages sorted from a single lung BrM exhibited a strong immunosuppressive activity, as previously shown for primary GBM. Finally, a significant expansion of some myeloid cell subsets was observed in the blood of both GBM and BrM patients. DISCUSSION: Our results define the main characteristics of the immune profile of BrM and GBM, which are distinguished by different levels of immunosuppressive myeloid cells and lymphocytes devoid of effector function. Understanding the role of the different cells in establishing the metastatic setting is critical for improving the therapeutic efficacy of new targeted immunotherapy strategies.
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