| Title: |
CD47 blockade-driven necroptosis complements BCL-2 inhibition-driven apoptosis in lymphoid malignancies |
| Authors: |
Chong, Stephen J. F.; Valentin, Rebecca; Wang, Jing; Zhu, Fen; Gokhale, Prafulla C.; Eschle, Benjamin K.; Garbicz, Filip; Iskandar, Kartini; Sewastianik, Tomasz; Toh, Brienne C. Y.; Penailillo, Johany; Peluso, Marisa O.; Zhang, Jeremy; Hackett, Liam; Collins, Mary C.; Lehmberg, Timothy Z.; Adam, Ammar; Zhang, Li; Armet, Caroline M.; Rausch, Matthew; Lee, Benjamin H.; Holland, Pamela M.; Palombella, Vito J.; Paterson, Alison M.; Kong, Li Ren; Hacken, Elisa ten; Guerriero, Jennifer L.; Herbaux, Charles; Wu, Catherine J.; Chng, Wee Joo; Pervaiz, Shazib; Niemann, Carsten U.; Carrasco, Ruben D.; Davids, Matthew S. |
| Source: |
Chong , S J F , Valentin , R , Wang , J , Zhu , F , Gokhale , P C , Eschle , B K , Garbicz , F , Iskandar , K , Sewastianik , T , Toh , B C Y , Penailillo , J , Peluso , M O , Zhang , J , Hackett , L , Collins , M C , Lehmberg , T Z , Adam , A , Zhang , L , Armet , C M , Rausch , M , Lee , B H , Holland , P M .... |
| Publication Year: |
2026 |
| Collection: |
University of Copenhagen: Research / Forskning ved Københavns Universitet |
| Description: |
Background Immune checkpoint blockade of CD47 has shown promising results in lymphoid malignancies, with its effects attributed to enabling tumor-cell phagocytosis. However, alternate cytotoxic cell death mechanisms have been reported, potentially contributing to the overall anti-tumor activity. Although previous studies have highlighted a mechanism of caspase-independent cell death, this mechanism has yet to be well-characterized, thereby warranting further investigation to comprehensively understand the anti-tumor mechanism of CD47 blockade to facilitate optimal drug partner selection for combination therapy. Methods The fully humanized anti-CD47 monoclonal antibodies, SRF231, magrolimab, as well as a mouse monoclonal anti-CD47 antibody, B6H12, were used. Multiple cell death mechanisms were evaluated including apoptosis, autophagy and necroptosis by using customized Hoechst/Annexin V, the precision medicine technique BH3 profiling, as well as standard experimental techniques – flow cytometry, siRNA and CRISPR Cas9 genetic manipulation, Western blotting, and immunohistochemistry. These techniques were used on a comprehensive range of lymphoid malignant models including diffuse large B-cell lymphoma, Burkitt lymphoma, and T-acute lymphoblastic leukemia cell lines, patient primary chronic lymphocytic leukemia cells, as well as lymphoid cell-line derived and patient-derived xenograft mice, to elucidate the mechanism of cell death by CD47 blockade and to identify the optimal drug partners for treatment combination. Results We demonstrate that the anti-CD47 antibodies SRF231, magrolimab, and B6H12 eliminated tumor cells from various in vitro and in vivo lymphoid malignant models via the activation of the RIPK1/MLKL/necroptotic pathway. Moreover, the BH3 profiling technique distinguished two different lymphoid malignant models that respond differently to the BCL-2 inhibitor venetoclax when combined with SRF231; one highlighting the effective yet distinct mechanisms of SRF231-induced necroptosis and venetoclax-induced ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| DOI: |
10.1186/s13045-025-01774-3 |
| Availability: |
https://researchprofiles.ku.dk/da/publications/1cc37925-91e3-4db4-a07c-9d585955da3d; https://doi.org/10.1186/s13045-025-01774-3; https://curis.ku.dk/ws/files/533168513/s13045-025-01774-3.pdf |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.B209ADB3 |
| Database: |
BASE |