In DLBCL models, mitochondrial remodeling and mitochondrial actin loss helped cells evade antibody-triggered complement killing.
Evidence
A CRISPR-Cas9 screen and mechanistic DLBCL cell studies, with patient-sample associations, linked mitochondrial damage, , and cytoskeletal markers to response.
Caveat
The evidence is mainly model-based, actin polymerization only partially overcame resistance, and the patient data were associative.
Simplified
(CDC) is an important effector function of various therapeutic antibodies. Cancer resistance to CDC is primarily attributed to extracellular factors. Using diffuse large B-cell lymphoma (DLBCL) models, we elucidated intracellular evasion mechanisms. By CRISPR-Cas9 library screening, we identified mitochondrial damage and as the key intracellular drivers of CDC. CDC resistance was linked to augmented mitochondrial mass, elongated mitochondria and reduced mitophagy, and decreased expression of actin-related genes. Actin downregulation in CDC-resistant cells occurred specifically within the mitochondria, connecting mitochondrial rearrangements and cytoskeletal dynamics with resistance. Stimulating actin polymerization could partially overcome CDC resistance. Of clinical significance, we observed a positive association between the cytoskeleton and antibody responses in DLBCL patient samples. In conclusion, our study unveils novel intracellular resistance mechanisms to antibody-induced CDC, highlighting the critical roles of mitochondrial rearrangements and cytoskeletal dynamics in CDC. We propose that decreased mitochondrial actin prevents overload of the mitophagy pathway, thereby reducing CDC.
Key numbers
20
Patient Cohort Size
Total number of DLBCL patients included in ex vivo assays.
429
Differentially Expressed Genes ()
Number of between high and low- responders in patient samples.
233
Survival Analysis Cohort
Number of newly diagnosed DLBCL cases analyzed for survival following R-CHOP therapy.
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Competing interests: GNM, MG, KK, MBO, KCMS, MGR, and ECWB are employees of Genmab and own Genmab warrants and/or stock. HJvdH, MBO, MEDC, ECWB, and TM are co-inventors on patents related to antibodies used in this study. MEDC consults for AbbVie, Novartis, and BYONDIS and has received research funding from AbbVie, BMS, Gilead, and Genmab. TM has received research support from Janssen Pharmaceuticals, Genmab, Takeda, Onkimmune, and Gilead.
