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

Akshay J. Patel, Zena N. Willsmore, Naeem Khan, Alex Richter, Babu Naidu, Mark T. Drayson, Sophie Papa, Andrew Cope, Sophia N. Karagiannis, Esperanza Perucha and Gary W. Middleton ()
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Akshay J. Patel: University of Birmingham
Zena N. Willsmore: King’s College London
Naeem Khan: University of Birmingham
Alex Richter: University of Birmingham
Babu Naidu: University of Birmingham
Mark T. Drayson: University of Birmingham
Sophie Papa: King’s College London
Andrew Cope: King’s College London
Sophia N. Karagiannis: King’s College London
Esperanza Perucha: King’s College London
Gary W. Middleton: University of Birmingham

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30863-x

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