Regulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade

Abstract

Checkpoint blockade with Pembrolizumab, has demonstrated durable clinical responses in advanced non-small cell lung cancer, however, treatment is offset by the development of high-grade immune related adverse events (irAEs) in some patients. Here, we show that in these patients a deficient Breg checkpoint fails to limit self-reactive T cell enhanced activity and auto-antibody formation enabled by PD-1/PD-L1 blockade, leading to severe auto-inflammatory sequelae. Principally a failure of IL-10 producing regulatory B cells as demonstrated through functional ex vivo assays and deep phenotyping mass cytometric analysis, is a major and significant finding in patients who develop high-grade irAEs when undergoing treatment with anti-PD1/PD-L1 checkpoint blockade. There is currently a lack of biomarkers to identify a priori those patients at greatest risk of developing severe auto-inflammatory syndrome. Pre-therapy B cell profiling could provide an important tool to identify lung cancer patients at high risk of developing severe irAEs on checkpoint blockade.

Checkpoint inhibitor immune-related adverse events: A focused review on autoantibodies and B cells as biomarkers, advancements and future possibilities

“…A longitudinal assessment of blood in an advanced lung cancer patient who developed late-onset irAEs on PD-1 inhibition, also reported increases in plasmablasts in circulation ( 119 ). Using functional ex vivo assays and mass cytometry analysis, defects in the regulatory B cell repertoire was found to predispose NSCLC patients to the development of immune related toxicity following anti-PD-1(L1) blockade ( 120 ). Notably, an attenuated presence of circulatory immunosuppressive B cell subsets (IL-10+, TGF-B+ PDL-1+) was observed in patients that developed toxicities compared to those that did not.…”

Immune-related adverse events in checkpoint blockade: Observations from human tissue and therapeutic considerations

“…B-cell depletion with the anti-CD20 monoclonal antibody rituximab has shown some promise for dermatological irAEs, with no apparent adverse impact on survival ( 104 ), and observations in inflammatory arthritis reviewed above arguably support interest in the approach. This should, however, be balanced against the general dearth of infiltrating B-cells in irAE tissues described herein, together with very recent data indicating that regulatory B-cells (Bregs), which would also be targeted by an anti-CD20 strategy, may play a critical role in the prevention of irAEs ( 105 ). A deficiency of this cell type in the circulation of CPI recipients was indeed predictive of subsequent toxicity in this study.…”

Germline genetic variation and predicting immune checkpoint inhibitor induced toxicity

“…Early diversification of T cell repertoire with decline in T cell clonality, increase in Th17 cells or early B cell changes have all been found to be associated with early development of irAE [82][83][84][85] . Deficiency in certain regulatory B cell phenotypes was found in patients who developed serious irAE 86 . Chaput et al showed that the composition of gut microbiota with Faecalibacterium and other Firmicutes has been associated with ipilimumab-induced colitis, whereas, the presence of Bacteroidetes was protective against colitis 87 .…”