Tumor-reactive antibodies evolve from non-binding and autoreactive precursors

Inhibiting DNA methylation improves antitumor immunity in ovarian cancer

“…These data support recent findings in clinical trials of immune checkpoint blockade in melanoma ( 21 ) and renal cell carcinoma ( 22 ), in which the presence of B cells and tertiary lymphoid structures predicts a response to immune therapy. In addition, a recent study found that the presence of IgG in high grade serous ovarian cancer tumors positively correlates with survival ( 23 ). B cells in these ovarian cancer tumors produce autoantibodies against proteins overexpressed by ovarian cancer, including MMP14 ( 23 ).…”

Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology

“…The tumor microenvironment contains antibody-secreting cells that are associated with a favorable prognosis in various cancer types (Zaenker et al, 2016;Helmink et al, 2020;Petitprez et al, 2020). For example, in patients with high-grade serous ovarian carcinoma, it was demonstrated that somatic hypermutations promoted antibody antitumor reactivity against certain surface autoantigens (Mazor et al, 2022). By using antibody-secreting cells within these tumors, cells were mutated and clonally expanded, resulting in the production of tumor-reactive antibodies against MT1-MMP (Mazor et al, 2022).…”

“…For example, in patients with high-grade serous ovarian carcinoma, it was demonstrated that somatic hypermutations promoted antibody antitumor reactivity against certain surface autoantigens (Mazor et al, 2022). By using antibody-secreting cells within these tumors, cells were mutated and clonally expanded, resulting in the production of tumor-reactive antibodies against MT1-MMP (Mazor et al, 2022). MT1-MMP has been demonstrated to be elevated in ovarian cancer compared with healthy tissues and, using multiple validation ELISA assays, a strong and reproducible antibody reactivity was detected in all tested patients (Mazor et al, 2022).…”

“…By using antibody-secreting cells within these tumors, cells were mutated and clonally expanded, resulting in the production of tumor-reactive antibodies against MT1-MMP (Mazor et al, 2022). MT1-MMP has been demonstrated to be elevated in ovarian cancer compared with healthy tissues and, using multiple validation ELISA assays, a strong and reproducible antibody reactivity was detected in all tested patients (Mazor et al, 2022). This work suggests a novel approach to the use of patient-derived antibodies either by selectively targeting MT1-MMP or as a drug delivery vehicle to tumors.…”

T cell help in the autoreactive germinal center

“…Aberrant epitope spreading might also contribute to both beneficial anti‐tumor immune responses 397–405 and adverse autoimmune events 406–410 following checkpoint blockade cancer immunotherapy. Paradoxically, epitope spreading and worse immune related adverse events (irAE) correlate with better anti‐tumor immunity 411–415 and anti‐tumor antibodies can evolve from pre‐existing autoantibodies through SHM, 416 suggesting that overcoming GC tolerance mechanisms might benefit cancer immunotherapy. TPH, TFH, and B cells have been identified in tumors and tumor associated TLS, and their presence correlates with improved survival 303,417–433 .…”