Tumor-infiltrating plasma cell profiling after PD-1 blockade reveals tumor-specific antibodies
Cancer Cell
R. Ryan Meyerhoff, Alan Chen, Jenny O’Brien, Carmen M. Anadon, Luis Uriel Lopez Bailon, Dayan Carrion-Estrada, Koravit Poysungnoen, Jared Lindenberger, Gabor Kemeny, Liliana Lyniv, Vaibjav Jain, Ricardo Chaurio, Noah Plappert, Tyler Evangelous, Chan Soo Park, Alok Sinha, Eziafa Oduah, Carolyn Glass, Kent Weinhold, Simon Gregory, John W. Hickey, Priyamvada Acharya, Neal Ready, Jose R. Conejo-Garcia, Wilton B. Williams, Scott J. Antonia
Summary
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.
Citation
Meyerhoff, R. Ryan, et al. “Tumor-infiltrating plasma cell profiling after PD-1 blockade reveals tumor-specific antibodies.” Cancer cell (2026).