Humoral contributions to checkpoint blockade therapy

Checkpoint blockade immunotherapy has changed the landscape of cancer treatment for many types of malignancies, but it still does not work for all individuals and for all tumor types. Much work over the past decade has been dedicated to discerning what underlies the heterogeneity in patient responses. While the underlying mechanism for checkpoint inhibition is mostly thought to be through facilitating better cellular immunity, Ring and colleagues recently began to broadly categorize the autoantibody landscape in immune checkpoint blockade (ICB)-treated individuals. They used the rapid extracellular antigen profiling technique to survey circulating antibody profiles from 374 patients and 131 healthy controls sampled longitudinally. The authors discovered that autoantibodies were more commonly found in patients with cancer treated with ICB compared with healthy controls, and that the types and levels of autoantibodies remained largely stable over time. While the population-level responses were quite diverse, there were some specific autoantigens that were targeted by the immune systems of multiple individuals. Of these, individuals who possessed autoantibodies against one or more proteins in the type-I interferon, interleukin (IL)-6 or IL-17 pathways or to tumor necrosis factor-like ligand 1A (TL1A) tended to have better responses to therapy, especially if the antibodies were neutralizing against their respective targets. Individuals who generated antibodies that blocked proteins within the bone morphogenesis pathway, conversely, exhibited a worse response to checkpoint inhibition. Overall, using this autoantibody-wide association study approach, the authors were able to characterize the extracellular and secreted autoreactome in detail, and to identify promising new therapeutic targets and areas of future investigation for patients taking ICB therapies.