Your browser doesn't support javascript.
loading
Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration.
Zhou, Yifan; Medik, Yusra B; Patel, Bhakti; Zamler, Daniel B; Chen, Sijie; Chapman, Thomas; Schneider, Sarah; Park, Elizabeth M; Babcock, Rachel L; Chrisikos, Taylor T; Kahn, Laura M; Dyevoich, Allison M; Pineda, Josue E; Wong, Matthew C; Mishra, Aditya K; Cass, Samuel H; Cogdill, Alexandria P; Johnson, Daniel H; Johnson, Sarah B; Wani, Khalida; Ledesma, Debora A; Hudgens, Courtney W; Wang, Jingjing; Wadud Khan, Md Abdul; Peterson, Christine B; Joon, Aron Y; Peng, Weiyi; Li, Haiyan S; Arora, Reetakshi; Tang, Ximing; Raso, Maria Gabriela; Zhang, Xuegong; Foo, Wai Chin; Tetzlaff, Michael T; Diehl, Gretchen E; Clise-Dwyer, Karen; Whitley, Elizabeth M; Gubin, Matthew M; Allison, James P; Hwu, Patrick; Ajami, Nadim J; Diab, Adi; Wargo, Jennifer A; Watowich, Stephanie S.
Afiliación
  • Zhou Y; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Medik YB; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Patel B; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Zamler DB; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Chen S; The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX.
  • Chapman T; Ministry of Education Key Lab of Bioinformatics and Bioinformatics Division, Beijing National Research Center for Information Science and Technology; Department of Automation, Tsinghua University, Beijing, China.
  • Schneider S; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Park EM; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Babcock RL; The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX.
  • Chrisikos TT; Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Kahn LM; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Dyevoich AM; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Pineda JE; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Wong MC; The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX.
  • Mishra AK; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Cass SH; The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX.
  • Cogdill AP; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Johnson DH; The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX.
  • Johnson SB; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Wani K; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Ledesma DA; The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX.
  • Hudgens CW; Platform for Innovative Microbiome and Translational Research, MD Anderson Cancer Center, Houston, TX.
  • Wang J; Platform for Innovative Microbiome and Translational Research, MD Anderson Cancer Center, Houston, TX.
  • Wadud Khan MA; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Peterson CB; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Joon AY; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Peng W; The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX.
  • Li HS; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Arora R; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Tang X; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Raso MG; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Zhang X; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Foo WC; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Tetzlaff MT; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Diehl GE; The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX.
  • Clise-Dwyer K; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Whitley EM; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Gubin MM; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Allison JP; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Hwu P; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Ajami NJ; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Diab A; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Wargo JA; Ministry of Education Key Lab of Bioinformatics and Bioinformatics Division, Beijing National Research Center for Information Science and Technology; Department of Automation, Tsinghua University, Beijing, China.
  • Watowich SS; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
J Exp Med ; 220(2)2023 02 06.
Article en En | MEDLINE | ID: mdl-36367776
ABSTRACT
Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)-mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4-mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.
Asunto(s)
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Interleucina-6 / Colitis Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Exp Med Año: 2023 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Interleucina-6 / Colitis Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Exp Med Año: 2023 Tipo del documento: Article