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. 2019 Oct 29;116(44):22246-22251.
doi: 10.1073/pnas.1908079116. Epub 2019 Oct 14.

Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities

Salahaldin A Tahir  1 , Jianjun Gao  1 , Yuji Miura  2 , Jorge Blando  3 , Rebecca S S Tidwell  4 , Hao Zhao  3 , Sumit K Subudhi  1 , Hussein Tawbi  5 , Emily Keung  6 , Jennifer Wargo  6 , James P Allison  7   8 , Padmanee Sharma  9   3   8
Affiliations

Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities

Salahaldin A Tahir et al. Proc Natl Acad Sci U S A. .

Abstract

Immune checkpoint (IC) therapy provides substantial benefits to cancer patients but can also cause distinctive toxicities termed immune-related adverse events (irAEs). Biomarkers to predict toxicities will be necessary to improve management of patients receiving IC therapy. We relied on serological analysis of recombinant cDNA expression libraries to evaluate plasma samples from patients treated with IC therapy and identified autoantibodies, both in pretreatment and on-treatment samples prior to the development of irAEs, which correlate with the development of immune-related hypophysitis (anti-GNAL and anti-ITM2B autoantibodies) and pneumonitis (anti-CD74 autoantibody). We developed an enzyme-linked immunosorbent assay and tested additional patient samples to confirm our initial findings. Collectively, our data suggest that autoantibodies may correlate with irAEs related to IC therapy, and specific autoantibodies may be detected early for the management of irAEs.

Keywords: autoimmune antibody; hypophysitis; immune checkpoint therapy; immune-related adverse events; pneumonitis.

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Conflict of interest statement

Competing interest statement: J.P.A. has ownership in Jounce, Neon, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Hummingbird, Dragonfly, Lytix, and Tvardi Therapeutics and serves as a consultant for Jounce, Kite Pharma, Neon, Amgen, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Tvardi Therapeutics, Lytix, Hummingbird, and Dragonfly. P.S. has ownership in Jounce, Neon, Constellation, Oncolytics, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Lytix, Hummingbird, and Dragonfly and serves as a consultant for Constellation, Jounce, Kite Pharma, Neon, BioAtla, Pieris Pharmaceuticals, Oncolytics Biotech, Merck, BioMx, Forty-Seven, Polaris, Apricity, Marker Therapeutics, Codiak, ImaginAb, Hummingbird, Lytix, and Dragonfly. J.G. serves as a consultant for ARMO Biosciences, AstraZeneca, CRISPR Therapeutics, Jounce, Nektar, Polaris, Pfizer, and Symphogen. C.G.D. and J.P.A. are coauthors on a 2016 workshop report.

Figures

Fig. 1.
Fig. 1.
Plasma anti-GNAL and anti-ITM2B autoantibodies correlate with IC-therapy–induced hypophysitis. (A) Schematic illustration of the SEREX-based identification of IC-therapy–induced toxicity-related autoantibodies and confirmation process. (B) Workflow to identify autoantigens (Ag) by SEREX and to confirm hypophysitis-related autoantibodies. (C) Anti-GNAL and (D) anti-ITM2B autoantibody fold change in response to IC therapy in the plasma of discovery cohort patients (hypophysitis = 3; without hypophysitis = 6). (E) Anti-GNAL and (F) anti-ITM2B autoantibody fold change in the plasma of confirmation cohort patients (hypophysitis = 5; without hypophysitis = 15). (G) Anti-GNAL autoantibody levels in pre- and posttreatment in the confirmation cohorts. Values represent pre- and posttreatment levels, and fold changes represent increase from baseline in response to IC therapy. All boxplots have median center values. *P < 0.05; **P < 0.01; ***P < 0.001.
Fig. 2.
Fig. 2.
Plasma anti-CD74 autoantibody correlates with IC-therapy–induced pneumonitis. (A) Workflow to identify autoantigens (Ag) by SEREX and to confirm pneumonitis-related autoantibodies. (B and C) Anti-CD74 autoantibody fold change in response to IC therapy in the plasma of the discovery (B) (pneumonitis = 2; without pneumonitis = 6) and the confirmation (C) (pneumonitis = 10; without pneumonitis = 22) cohorts. (D) Anti-CD74 autoantibody levels in pre- and posttreatment in the confirmation cohort. Values represent pre- and posttreatment levels, and fold changes represent the increase from baseline in response to IC therapy. All boxplots have median center values. **P < 0.01; ***P < 0.001.
Fig. 3.
Fig. 3.
GNAL and ITM2B are expressed in normal human pituitary gland tissue and increased expression of CD74 in the lung of a pneumonitis patient. (A and B) IHC staining of normal human pituitary gland shows GNAL (A) and ITM2B (B) expression on the glandular epithelium. Arrows indicate the expression levels: (a) strong, (b) moderate, (c) light, and (d) negative. (C) IHC staining of human lung shows considerably higher expression of CD74 in the lung of a patient with IC-therapy–induced pneumonitis than that in a normal lung.
See this image and copyright information in PMC

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