Cancer Cell |源自 PD-1 诱导NSCLC浆细胞的抗体构建新型 CAR-T，靶向瓜氨酸化抗原增强肿瘤杀伤
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TL;DR — A Cancer Cell study mined tumor-infiltrating plasma cells from NSCLC patients treated with neoadjuvant pembrolizumab (TOP1501 trial) to clone a native human antibody, PC-1, that recognizes citrullinated tumor antigens, then converted it into a CAR-T that kills tumor cells and immunosuppressive myeloid cells. It shows patient-intrinsic humoral immunity can be a discovery engine for solid-tumor CAR targets.
- Single-cell RNA-seq plus paired full-length BCR sequencing of 7,150 tumor B cells (3 patients) resolved 7 subsets spanning naive→GC→memory/atypical memory→ASC, with high somatic hypermutation and shared clonal lineages; CODEX imaging showed PD-1 blockade drove mature, Ki67+ germinal-center-like tertiary lymphoid structures and diffuse CD138+CD38+ plasma cell infiltration.
- Recombinant expression of 15 highly expanded ASC antibodies gave 73% tumor-surface binders (Calu-6); a broader 29-antibody panel across GC/memory/low-expansion ASC clones gave ~52% binders (A549), showing tumor reactivity spans multiple antigen-experienced subsets, not just terminal plasma cells.
- IP–MS, ELISA and SPR identified PC-1's target as citrullinated vimentin (plus citrullinated calreticulin, p53, Hsp90) at nanomolar affinity (~10⁻⁸ M); it does not bind unmodified protein, cyclic citrullinated peptide, or lupus/Sjögren autoantigens, and HuProt array (23,004 proteins) showed binding to only 0.6%. A 2.2 Å apo Fab structure plus docking indicated long, aromatic/polar-rich CDRs suited to conformational citrullination epitopes; germline-reverted PC-1 bound far more weakly, so specificity is affinity-maturation-derived.
- PC-1 CAR-T (CD28 or 4-1BB) killed Calu-6/A427 in vitro (>80% cell-index drop for CD28) and suppressed growth in NSG xenografts; CRISPR PAD2 knockout collapsed PC-1 binding from 82.6% to 6.4% and abolished killing, confirming citrullination dependence, with murinized CAR-T active in immunocompetent models and no detectable off-target toxicity reported.
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Cancer Cell |源自 PD-1 诱导NSCLC浆细胞的抗体构建新型 CAR-T，靶向瓜氨酸化抗原增强肿瘤杀伤
TL;DR — A Cancer Cell study mined tumor-infiltrating plasma cells from NSCLC patients treated with neoadjuvant pembrolizumab (TOP1501 trial) to clone a native human antibody, PC-1, that recognizes citrullinated tumor antigens, then converted it into a CAR-T that kills tumor cells and immunosuppressive myeloid cells. It shows patient-intrinsic humoral immunity can be a discovery engine for solid-tumor CAR targets.
- Single-cell RNA-seq plus paired full-length BCR sequencing of 7,150 tumor B cells (3 patients) resolved 7 subsets spanning naive→GC→memory/atypical memory→ASC, with high somatic hypermutation and shared clonal lineages; CODEX imaging showed PD-1 blockade drove mature, Ki67+ germinal-center-like tertiary lymphoid structures and diffuse CD138+CD38+ plasma cell infiltration.
- Recombinant expression of 15 highly expanded ASC antibodies gave 73% tumor-surface binders (Calu-6); a broader 29-antibody panel across GC/memory/low-expansion ASC clones gave ~52% binders (A549), showing tumor reactivity spans multiple antigen-experienced subsets, not just terminal plasma cells.
- IP–MS, ELISA and SPR identified PC-1's target as citrullinated vimentin (plus citrullinated calreticulin, p53, Hsp90) at nanomolar affinity (~10⁻⁸ M); it does not bind unmodified protein, cyclic citrullinated peptide, or lupus/Sjögren autoantigens, and HuProt array (23,004 proteins) showed binding to only 0.6%. A 2.2 Å apo Fab structure plus docking indicated long, aromatic/polar-rich CDRs suited to conformational citrullination epitopes; germline-reverted PC-1 bound far more weakly, so specificity is affinity-maturation-derived.
- PC-1 CAR-T (CD28 or 4-1BB) killed Calu-6/A427 in vitro (>80% cell-index drop for CD28) and suppressed growth in NSG xenografts; CRISPR PAD2 knockout collapsed PC-1 binding from 82.6% to 6.4% and abolished killing, confirming citrullination dependence, with murinized CAR-T active in immunocompetent models and no detectable off-target toxicity reported.