Tumor-infiltrating plasma cell profiling after PD-1 blockade reveals tumor-specific antibodies
(1) Meyerhoff RR (2) Chen A (3) O'Brien J (4) Anadon CM (5) Lopez Bailon LU (6) Carrion-Estrada D (7) Poysungnoen K (8) Lindenberger J (9) Kemeny G (10) Lyniv L (11) Jain V (12) Chaurio R (13) Plappert N (14) Evangelous T (15) Park CS (16) Sinha A (17) Oduah E (18) Glass C (19) Weinhold K (20) Gregory S (21) Hickey JW (22) Acharya P (23) Ready N (24) Conejo-Garcia JR (25) Williams WB (26) Antonia SJ
Evaluating patient NSCLC tumors treated with neoadjuvant anti-PD-1 and enriched for tertiary lymphoid structures, Meyerhoff, Chen, and O’brien et al. used transcriptomic data to identify B cell populations, including CD138+ plasma cells, and then performed single-cell sequencing to identify tumor-targeting BCRs and generate recombinant antibodies. The lead antibody, PC-1, recognized citrullinated antigens on tumor and pro-tumor myeloid cells, dependent on their expression of the citrullination enzyme PAD2. Incorporation of PC-1 into a CAR T cell mediated tumor control in mouse models, without evidence of off-tumor toxicity.
Contributed by Lauren Hitchings
(1) Meyerhoff RR (2) Chen A (3) O'Brien J (4) Anadon CM (5) Lopez Bailon LU (6) Carrion-Estrada D (7) Poysungnoen K (8) Lindenberger J (9) Kemeny G (10) Lyniv L (11) Jain V (12) Chaurio R (13) Plappert N (14) Evangelous T (15) Park CS (16) Sinha A (17) Oduah E (18) Glass C (19) Weinhold K (20) Gregory S (21) Hickey JW (22) Acharya P (23) Ready N (24) Conejo-Garcia JR (25) Williams WB (26) Antonia SJ
Evaluating patient NSCLC tumors treated with neoadjuvant anti-PD-1 and enriched for tertiary lymphoid structures, Meyerhoff, Chen, and O’brien et al. used transcriptomic data to identify B cell populations, including CD138+ plasma cells, and then performed single-cell sequencing to identify tumor-targeting BCRs and generate recombinant antibodies. The lead antibody, PC-1, recognized citrullinated antigens on tumor and pro-tumor myeloid cells, dependent on their expression of the citrullination enzyme PAD2. Incorporation of PC-1 into a CAR T cell mediated tumor control in mouse models, without evidence of off-tumor toxicity.
Contributed by Lauren Hitchings
ABSTRACT: The role of tumor-infiltrating B cells (TIL-Bs) in shaping anti-tumor responses in the context of immune checkpoint blockade remains incompletely understood. Here, we interrogate the humoral response in resected lung tumors from patients with non-small cell lung cancer (NSCLC) treated with neoadjuvant PD-1 blockade. We find that tumors orchestrate tertiary lymphoid structures with CD138(+) plasma cells, from which we clone recombinant monoclonal antibodies (mAbs) using B cell receptors (BCRs) exhibiting somatic hypermutation and class switching. Several mAbs bind cell-surface citrullinated proteins, characteristic of cancer cells. Chimeric antigen receptor (CAR) T redirected with the soluble chain fragment variable (scFv) of our lead candidate antibody (PC-1) specifically target tumor cells and tumor-promoting myeloid cells in vivo without off-target activity. Moreover, ablation of the citrullination enzyme PADI2 in tumor-bearing mice eliminates reactivity to PC-1 and cytotoxic killing by the CAR. Our results implicate a therapeutic potential for tumor-infiltrating plasma cells that may be harnessed for cancer treatment.
Author Info:
(1) Division of Interventional Radiology, Department of Radiology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: meyerhr@mskcc.org. (2) Division of
Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (3) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (4) Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA. (5) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (6) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (7) Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA. (8) Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA. (9) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (10) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (11) Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA. (12) Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA. (13) Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA. (14) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. (15) Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA. (16) Department of Chemistry, Duke University, Durham, NC 27710, USA; Department of Computer Science, Duke University, Durham, NC 27710, USA. (17) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (18) Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA. (19) Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA. (20) Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA. (21) Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA. (22) Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. (23) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (24) Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA. (25) Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: wilton.williams@duke.edu. (26) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: scott.antonia@duke.edu.
