Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade

Miles C. Andrews, Connie P.M. Duong, Vancheswaran Gopalakrishnan, Valerio Iebba, Wei Shen Chen, Lisa Derosa, Md Abdul Wadud Khan, Alexandria P. Cogdill, Michael G. White, Matthew C. Wong, Gladys Ferrere, Aurélie Fluckiger, Maria P. Roberti, Paule Opolon, Maryam Tidjani Alou, Satoru Yonekura, Whijae Roh, Christine N. Spencer, Irina Fernandez Curbelo, Luis VenceAlexandre Reuben, Sarah Johnson, Reetakshi Arora, Golnaz Morad, Matthew Lastrapes, Erez N. Baruch, Latasha Little, Curtis Gumbs, Zachary A. Cooper, Peter A. Prieto, Khalida Wani, Alexander J. Lazar, Michael T. Tetzlaff, Courtney W. Hudgens, Margaret K. Callahan, Matthew Adamow, Michael A. Postow, Charlotte E. Ariyan, Pierre Olivier Gaudreau, Luigi Nezi, Didier Raoult, Catalin Mihalcioiu, Arielle Elkrief, Rossanna C. Pezo, Lauren E. Haydu, Julie M. Simon, Hussein A. Tawbi, Jennifer McQuade, Patrick Hwu, Wen Jen Hwu, Rodabe N. Amaria, Elizabeth M. Burton, Scott E. Woodman, Stephanie Watowich, Adi Diab, Sapna P. Patel, Isabella C. Glitza, Michael K. Wong, Li Zhao, Jianhua Zhang, Nadim J. Ajami, Joseph Petrosino, Robert R. Jenq, Michael A. Davies, Jeffrey E. Gershenwald, P. Andrew Futreal, Padmanee Sharma, James P. Allison, Bertrand Routy, Laurence Zitvogel, Jennifer A. Wargo

Research output: Contribution to journalArticlepeer-review


Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

Original languageEnglish
Pages (from-to)1432-1441
Number of pages10
JournalNature Medicine
Issue number8
Publication statusPublished - Aug 2021

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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