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Radiotherapy upregulates the expression of membrane-bound negative complement regulator proteins on tumor cells and limits complement-mediated tumor cell lysis

Background/Objectives: Radiotherapy (RT) is a mainstay of clinical cancer therapy that causes broad immune responses. The complement system is a pivotal effector mechanism in the innate immune response, but the impact of RT is less well understood. This study investigates the interaction between RT...

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Main Authors: Liang, Yingying (Author) , Mai, Lixin (Author) , Schneeweiss, Jonathan M. (Author) , Lopez Perez, Ramon (Author) , Kirschfink, Michael (Author) , Huber, Peter E. (Author)
Format: Article (Journal)
Language:English
Published: 18 July 2025
In: Cancers
Year: 2025, Volume: 17, Issue: 14, Pages: 1-15
ISSN:2072-6694
DOI:10.3390/cancers17142383
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.3390/cancers17142383
Verlag, kostenfrei, Volltext: https://www.mdpi.com/2072-6694/17/14/2383
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Author Notes:Yingying Liang, Lixin Mai, Jonathan M. Schneeweiss, Ramon Lopez Perez, Michael Kirschfink and Peter E. Huber

MARC

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520 |a Background/Objectives: Radiotherapy (RT) is a mainstay of clinical cancer therapy that causes broad immune responses. The complement system is a pivotal effector mechanism in the innate immune response, but the impact of RT is less well understood. This study investigates the interaction between RT and the complement system as a possible approach to improve immune responses in cancer treatment. Methods: Human solid cancer (lung, prostate, liver, breast cancer), lymphoma, and leukemia cells were irradiated using X-rays and treated with polyclonal antibodies or anti-CD20 monoclonal antibodies, respectively. Chromium release assay was applied to measure cell lysis after radiation with or without complement-activating antibody treatment. The expression of membrane-bound complement regulatory proteins (mCRPs; CD46, CD55, CD59), which confer resistance against complement activation, CD20 expression, apoptosis, and radiation-induced DNA double-strand breaks (γH2AX), was measured by flow cytometry. The radiosensitivity of tumor cells was assessed by colony-forming assay. Results: We demonstrate that RT profoundly impacts complement function by upregulating the expression of membrane-bound complement regulatory proteins (mCRPs) on tumor cells in a dose- and time-dependent manner. Impaired complement-mediated tumor cell lysis could thus potentially contribute to radio-therapeutic resistance. We also observed RT-induced upregulation of CD20 expression on lymphoma and leukemic cells. Notably, complement activation prior to RT proved more effective in inducing RT-dependent early apoptosis compared to post-irradiation treatment. While complement modulation does not significantly alter RT-induced DNA-damage repair mechanisms or intrinsic radiosensitivity in cancer cells, our results suggest that combining RT with complement-based anti-cancer therapy may enhance complement-dependent cyto-toxicity (CDC) and apoptosis in tumor cells. Conclusions: This study sheds light on the complex interplay between RT and the complement system, offering insights into potential novel combinatorial therapeutic strategies and a potential sequential structure for certain tumor types. 
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