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

TY - JOUR

T1 - Regulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade

AU - Patel, Akshay J

AU - Willsmore, Zena N

AU - Khan, Naeem

AU - Richter, Alex

AU - Naidu, Babu

AU - Drayson, Mark T

AU - Papa, Sophie

AU - Cope, Andrew

AU - Karagiannis, Sophia N

AU - Perucha, Esperanza

AU - Middleton, Gary W

N1 - Funding Information: The authors would like to acknowledge the advice and support of Francis J. Mussai, Benjamin Willcox, and Carrie Willcox. The authors acknowledge support by the Cancer Research UK King’s Health Partners Centre at King’s College London (C604/A25135); the CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587). The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London (IS-BRC-1215-20006). In addition, we acknowledge further support from Cancer Research UK at the University of Birmingham (CRUK Pre-doctoral bursary— A.J.P.). The authors are solely responsible for study design, data collection, analysis, decision to publish and preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. BRC Funding (36624) for the PAIR Study. Funding Information: The authors would like to acknowledge the advice and support of Francis J. Mussai, Benjamin Willcox, and Carrie Willcox. The authors acknowledge support by the Cancer Research UK King’s Health Partners Centre at King’s College London (C604/A25135); the CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587). The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London (IS-BRC-1215-20006). In addition, we acknowledge further support from Cancer Research UK at the University of Birmingham (CRUK Pre-doctoral bursary— A.J.P.). The authors are solely responsible for study design, data collection, analysis, decision to publish and preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. BRC Funding (36624) for the PAIR Study. Publisher Copyright: © 2022, The Author(s).

PY - 2022/6/7

Y1 - 2022/6/7

N2 - 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.

AB - 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.

KW - B-Lymphocytes, Regulatory

KW - B7-H1 Antigen/genetics

KW - Carcinoma, Non-Small-Cell Lung/drug therapy

KW - Humans

KW - Lung Neoplasms/drug therapy

KW - Programmed Cell Death 1 Receptor/genetics

UR - http://www.scopus.com/inward/record.url?scp=85131479628&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-30863-x

DO - 10.1038/s41467-022-30863-x

M3 - Article

C2 - 35672305

SN - 2041-1723

VL - 13

SP - 3148

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3148

ER -