PO.TB06.01 · 肿瘤生物学
肺肿瘤微环境内放疗介导的补体级联激活削弱放射治疗的疗效
Radiation-mediated complement cascade activation within the lung tumor microenvironment diminishes the efficacy of radiation therapy
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摘要 Abstract
中文摘要
非小细胞肺癌（NSCLC）是全球癌症相关死亡的首要原因，亟需新型干预措施以提高生存率。目前局部晚期NSCLC的治疗方式包括细胞毒性化疗联合同步外照射放疗（XRT），随后进行免疫治疗。然而，XRT对补体系统（先天免疫的关键组成部分）的影响仍不明确。补体调节蛋白（CRPs），包括CD46、CD55和CD59，严密调控由三条通路介导的补体激活。在本研究中，我们研究了NSCLC细胞系体外及体内肿瘤微环境（TME）内CRPs的表面表达。我们评估了TME中三条补体通路的激活情况，并监测了C57BL/6野生型、C3-/-和C3AR-/-小鼠在XRT后的肿瘤生长和生存情况。XRT后，NSCLC细胞系A549和H460的细胞表面CD46、CD59和CD55表达较对照显著增加（p<0.05），而正常肺上皮细胞（MRC5）未表现出这种上调。野生型小鼠中经照射的Lewis肺癌（LLC）肿瘤显示C3和C5 mRNA及蛋白水平升高（p=0.0013）。此外，与假照射相比，经照射的LLC肿瘤中C3AR和C5AR显著上调。另外，XRT后LLC的TME中替代补体通路成分因子B和因子D显著上调（p<0.001）。然而，与假照射相比，XRT处理的LLC肿瘤中膜攻击复合物（MAC）未形成。C3-/-和C3AR-/-小鼠中中心补体成分C3和C3AR的缺失联合XRT可延缓LLC肿瘤生长。我们的研究结果表明XRT增加NSCLC中CRPs的表达，可能促进肿瘤细胞的免疫逃逸。我们还发现补体系统替代通路的激活。靶向C3和C3AR有效延缓了肿瘤生长，凸显了补体通路调控在增强NSCLC中XRT疗效方面的潜力。这些结果强调了阐明放疗诱导的补体激活与肿瘤生存之间复杂相互作用的重要性，以制定NSCLC的新型治疗策略。
查看英文原文 English abstract
Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related mortality worldwide, necessitating novel interventions to improve survival rates. Current treatment modalities for locally advanced NSCLC involve cytotoxic chemotherapy with concurrent external beam radiation therapy (XRT), followed by immunotherapy. However, the impact of XRT on the complement system, a crucial component of innate immunity, remains unclear. The complement regulatory proteins (CRPs), including CD46, CD55, and CD59, tightly control complement activation mediated by the three pathways. In this study, we investigated the surface expression of CRPs in NSCLC cell lines in vitro and within the tumor microenvironment (TME) in vivo . We assessed the activation of the three complement pathways in the TME and monitored tumor growth and survival in C57BL/6 wild-type, C3 -/- , and C3AR -/- mice following XRT. Following XRT, NSCLC cell lines A549 and H460 exhibited a significant increase in the cell surface expression of CD46, CD59, and CD55 compared to controls (p<0.05), whereas normal lung epithelial cells (MRC5) did not display such upregulation. Irradiated Lewis lung carcinoma (LLC) tumors in wild-type mice demonstrated elevated levels of C3 and C5 mRNA and protein (p=0.0013). Also, C3AR and C5AR were significantly upregulated in the irradiated LLC tumor as compared to the sham. Additionally, the alternative complement pathway components, factor B and factor D, were significantly upregulated (p<0.001) in the LLC TME following XRT. However, the membrane attack complex (MAC) did not form in XRT-treated LLC tumors compared to sham. Deficiency of the central C3 and C3AR complement components in C3 -/ - and C3AR -/- mice delays LLC tumor growth in combination with XRT. Our findings suggest that XRT increases the expression of CRPs in NSCLC, potentially facilitating immune evasion by tumor cells. We also found activation of the alternative pathway of the complement system. Targeting C3 and C3AR effectively delayed tumor growth, highlighting the potential of complement pathway modulation to enhance the efficacy of XRT in NSCLC treatment. These results underscore the importance of elucidating the intricate interplay between radiation-induced complement activation and tumor survival for devising novel therapeutic strategies in NSCLC.
利益披露 Disclosure
H. Shah, None..
M. Saikia, None..
X. Wu, None..
J. P. Atkinson, None..
A. K. Singh, None..
V. Kapoor, None.