TY  - JOUR
AU  - Liang, Yingying
AU  - Mai, Lixin
AU  - Schneeweiss, Jonathan
AU  - Lopez Perez, Ramon
AU  - Kirschfink, Michael
AU  - Huber, Peter
TI  - Radiotherapy Upregulates the Expression of Membrane-Bound Negative Complement Regulator Proteins on Tumor Cells and Limits Complement-Mediated Tumor Cell Lysis.
JO  - Cancers
VL  - 17
IS  - 14
SN  - 2072-6694
CY  - Basel
PB  - MDPI
M1  - DKFZ-2025-01579
SP  - 2383
PY  - 2025
N1  - #EA:E055#LA:E055#
AB  - 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.
KW  - CD20 (Other)
KW  - DNA-damage repair (Other)
KW  - complement activation (Other)
KW  - complement-dependent cytotoxicity (CDC) (Other)
KW  - membrane-bound complement regulatory proteins (mCRPs) (Other)
KW  - radiosensitivity (Other)
KW  - radiotherapy (Other)
KW  - timing (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40723265
DO  - DOI:10.3390/cancers17142383
UR  - https://inrepo02.dkfz.de/record/303228
ER  -