%0 Journal Article
%A Liang, Yingying
%A Mai, Lixin
%A Schneeweiss, Jonathan
%A Lopez Perez, Ramon
%A Kirschfink, Michael
%A Huber, Peter
%T Radiotherapy Upregulates the Expression of Membrane-Bound Negative Complement Regulator Proteins on Tumor Cells and Limits Complement-Mediated Tumor Cell Lysis.
%J Cancers
%V 17
%N 14
%@ 2072-6694
%C Basel
%I MDPI
%M DKFZ-2025-01579
%P 2383
%D 2025
%Z #EA:E055#LA:E055#
%X 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 radiotherapeutic 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 cytotoxicity (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.
%K CD20 (Other)
%K DNA-damage repair (Other)
%K complement activation (Other)
%K complement-dependent cytotoxicity (CDC) (Other)
%K membrane-bound complement regulatory proteins (mCRPs) (Other)
%K radiosensitivity (Other)
%K radiotherapy (Other)
%K timing (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40723265
%R 10.3390/cancers17142383
%U https://inrepo02.dkfz.de/record/303228