Humoral determinants of checkpoint immunotherapy: anti-TL1A treatment has a synergistic effect with anti-PD-1 treatment

While the role of cellular immunity in checkpoint immunotherapy (CPI) for cancer is well established, the impact of antibody-mediated humoral immunity is comparably underexplored. Here we used rapid extracellular antigen profiling (REAP) to map the autoantibody reactome within a cohort of 374 cancer patients treated with CPIs and 131 healthy controls for autoantibodies against 6,172 extracellular and secreted proteins (the ‘exoproteome’). Globally, CPI-treated cancer patients harbored an exquisite diversity of autoreactivities that were elevated relative to controls, but changed minimally with treatment. Autoantibody signatures within CPI-treated patients strikingly distinguished them from controls. While associations of specific autoantibodies with immune-related adverse events (irAE) were sparse, we detected numerous individual autoantibodies that were associated with dramatically altered odds ratios (ORs) for response to therapy. These included autoantibodies against immunomodulatory proteins, such as cytokines, growth factors, and immunoreceptors, as well as tumor surface proteins. Functional evaluation of several autoantibody responses indicated that they neutralized the activity of their target proteins including type-I IFN (IFN-I), IL-6, OSM, TL1A, and BMPR1A/BMPR2. Modeling the effects of autoantibodies against IFN-I and TL1A in preclinical mouse tumor models resulted in enhanced CPI efficacy, consistent with their effects in patients. This single-cell RNA sequencing dataset evaluates the synergistic effect between anti-PD-1 and anti-TL1A treatments.