Patient-derived IgG Amplifies Fcγ Receptor-Dependent Colonic Inflammation During Immune Checkpoint Blockade
- 1New York University Langone Medical Center
Abstract
Immune-related adverse events (irAEs), particularly colitis, are major limitations of immune checkpoint inhibitor (ICI) therapy, but their mechanisms remain poorly understood. Here we show that endogenous autoantibodies (AAbs) can promote ICI-associated colitis through Fcγ receptor-dependent pathways. IgG from melanoma patients treated with pembrolizumab, nivolumab, or ipilimumab, with or without severe colitis, was transferred into wild-type or humanized FcγR (hFcγR) mice receiving comparable ICI therapy. Wild-type mice did not develop changes in the colon. In contrast, hFcγR mice given IgG from patients with colitis developed colon inflammation marked by a significant increase in submucosal lymphocyte infiltration, goblet cell loss, and circulating cytokines, including IL-1β, IL-17a, and IL-22. Single-cell RNA sequencing identified an IgG-regulated inflammatory network involving IFNγ-producing ILC1, Th1 and cytotoxic T cells, IL-1β+ M1 macrophages, plasma B cells/plasmablasts, and IL-22-producing ILC3-LTi cells. Patient serum autoantibody profiling further identified CCR5 and CXCR4 receptors as candidate immune-related targets associated with ICC susceptibility. Immune-related adverse events (irAEs), particularly colitis, are major limitations of immune checkpoint inhibitor (ICI) therapy, but their mechanisms remain poorly understood. Here we show that endogenous autoantibodies (AAbs) can promote ICI-associated colitis through Fc gamma receptor (FcgR)-dependent pathways. IgG from melanoma patients treated with pembrolizumab, nivolumab, or ipilimumab, with or without severe colitis, was transferred into wild-type or humanized FcgR (hFcgR) mice receiving comparable ICI therapy. Wild-type mice did not develop changes in the colon. In contrast, hFcgR mice given IgG from patients with colitis developed colon inflammation marked by a significant increase in submucosal lymphocyte infiltration, goblet cell loss, and circulating cytokines, including IL-6, IL-17, and IL-22. Single-cell RNA sequencing identified an IgG-regulated inflammatory network involving IFNg-producing ILC1, Th1 and cytotoxic T cells, IL-1betta-M1 macrophages, plasma B cells/plasmablasts, and IL-22-producing ILC3-LTi cells. Patient serum autoantibody profiling further identified CCR5 and CXCR4 receptors as candidate immune-related targets associated with ICC susceptibility.
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BibTeX
@misc{voloshyna2026patientderived,
title = {{Patient-derived IgG Amplifies Fcγ Receptor-Dependent Colonic Inflammation During Immune Checkpoint Blockade}},
author = {I. Voloshyna and Y. Patskovsky and S. Sandigursky and C. Sreenivasaiah and E. C. Bayrakta and E. Tardio and A. V. Lopez and S. Idga and C. Ng and M. Ibrahim and C. Goldberg and A. Zhurova and R. Freih and J. Mastroianni and Y. Hao and P. Mishra and A. Khodadadi-Jamayran and J. Mehnert and G. J. Silverman and F. Fa'ak and I. Osman and M. Krogsgaard},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.03.729692},
url = {https://www.biorxiv.org/content/10.64898/2026.06.03.729692v2},
note = {Public domain},
}
RIS
TY - UNPB
TI - Patient-derived IgG Amplifies Fcγ Receptor-Dependent Colonic Inflammation During Immune Checkpoint Blockade
AU - I. Voloshyna
AU - Y. Patskovsky
AU - S. Sandigursky
AU - C. Sreenivasaiah
AU - E. C. Bayrakta
AU - E. Tardio
AU - A. V. Lopez
AU - S. Idga
AU - C. Ng
AU - M. Ibrahim
AU - C. Goldberg
AU - A. Zhurova
AU - R. Freih
AU - J. Mastroianni
AU - Y. Hao
AU - P. Mishra
AU - A. Khodadadi-Jamayran
AU - J. Mehnert
AU - G. J. Silverman
AU - F. Fa'ak
AU - I. Osman
AU - M. Krogsgaard
PY - 2026
DA - 2026/06/03
PB - bioRxiv
DO - 10.64898/2026.06.03.729692
UR - https://www.biorxiv.org/content/10.64898/2026.06.03.729692v2
AB - Immune-related adverse events (irAEs), particularly colitis, are major limitations of immune checkpoint inhibitor (ICI) therapy, but their mechanisms remain poorly understood. Here we show that endogenous autoantibodies (AAbs) can promote ICI-associated colitis through Fcγ receptor-dependent pathways. IgG from melanoma patients treated with pembrolizumab, nivolumab, or ipilimumab, with or without severe colitis, was transferred into wild-type or humanized FcγR (hFcγR) mice receiving comparable ICI therapy. Wild-type mice did not develop changes in the colon. In contrast, hFcγR mice given IgG from patients with colitis developed colon inflammation marked by a significant increase in submucosal lymphocyte infiltration, goblet cell loss, and circulating cytokines, including IL-1β, IL-17a, and IL-22. Single-cell RNA sequencing identified an IgG-regulated inflammatory network involving IFNγ-producing ILC1, Th1 and cytotoxic T cells, IL-1β+ M1 macrophages, plasma B cells/plasmablasts, and IL-22-producing ILC3-LTi cells. Patient serum autoantibody profiling further identified CCR5 and CXCR4 receptors as candidate immune-related targets associated with ICC susceptibility. Immune-related adverse events (irAEs), particularly colitis, are major limitations of immune checkpoint inhibitor (ICI) therapy, but their mechanisms remain poorly understood. Here we show that endogenous autoantibodies (AAbs) can promote ICI-associated colitis through Fc gamma receptor (FcgR)-dependent pathways. IgG from melanoma patients treated with pembrolizumab, nivolumab, or ipilimumab, with or without severe colitis, was transferred into wild-type or humanized FcgR (hFcgR) mice receiving comparable ICI therapy. Wild-type mice did not develop changes in the colon. In contrast, hFcgR mice given IgG from patients with colitis developed colon inflammation marked by a significant increase in submucosal lymphocyte infiltration, goblet cell loss, and circulating cytokines, including IL-6, IL-17, and IL-22. Single-cell RNA sequencing identified an IgG-regulated inflammatory network involving IFNg-producing ILC1, Th1 and cytotoxic T cells, IL-1betta-M1 macrophages, plasma B cells/plasmablasts, and IL-22-producing ILC3-LTi cells. Patient serum autoantibody profiling further identified CCR5 and CXCR4 receptors as candidate immune-related targets associated with ICC susceptibility.
ER -