Incidence of B cell malignancies in patients with lung cancer receiving PD-1 blockade therapy.

Abstract

Many patients with various cancers have received immune checkpoint inhibitors (ICIs) worldwide since their approval, and novel unexpected complications from their long-term use are apparent. We identified some cases of B cell lymphoma occurring during PD-1 blockade therapy as such unexpected complications. In this study, we aimed to evaluate the incidence of hematological malignancies in patients with lung cancer receiving PD-1 blockade therapy and to elucidate the mechanisms underlying the progression of these malignancies. We performed immunohistochemical staining on the clinical samples from patients with B cell lymphoma that developed during PD-1 blockade therapy and analyzed large-scale real-world datasets. We further investigated the underlying mechanisms through in vitro and in vivo experiments. A higher incidence of B cell malignancies has been observed in patients with lung cancer treated with PD-1 blockade therapies based on large-scale real-world data analyses (n = 15,670). Our identified lymphomas had a large amount of CD4+ T follicular helper (TFH)-cell infiltration. In addition, PD-1 blockade activated PD-1+ TFH cells, which promoted lymphoma proliferation via the IL-4/IL-4R, IL-21/IL-21R, and CD40L/CD40 axes. Notably, the lymphomas exhibited high expression of IL-4R, IL-21R, and CD40. Our findings highlight the need for careful monitoring and consideration of the potential B-cell malignancy complications in clinical settings where ICIs are used.