학술논문
Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade
Document Type
Article
Author
Andrews, Miles C.; Duong, Connie P. M.; Gopalakrishnan, Vancheswaran; Iebba, Valerio; Chen, Wei-Shen; Derosa, Lisa; Khan, Md Abdul Wadud; Cogdill, Alexandria P.; White, Michael G.; Wong, Matthew C.; Ferrere, Gladys; Fluckiger, Aurélie; Roberti, Maria P.; Opolon, Paule; Alou, Maryam Tidjani; Yonekura, Satoru; Roh, Whijae; Spencer, Christine N.; Curbelo, Irina Fernandez; Vence, Luis; Reuben, Alexandre; Johnson, Sarah; Arora, Reetakshi; Morad, Golnaz; Lastrapes, Matthew; Baruch, Erez N.; Little, Latasha; Gumbs, Curtis; Cooper, Zachary A.; Prieto, Peter A.; Wani, Khalida; Lazar, Alexander J.; Tetzlaff, Michael T.; Hudgens, Courtney W.; Callahan, Margaret K.; Adamow, Matthew; Postow, Michael A.; Ariyan, Charlotte E.; Gaudreau, Pierre-Olivier; Nezi, Luigi; Raoult, Didier; Mihalcioiu, Catalin; Elkrief, Arielle; Pezo, Rossanna C.; Haydu, Lauren E.; Simon, Julie M.; Tawbi, Hussein A.; McQuade, Jennifer; Hwu, Patrick; Hwu, Wen-Jen; Amaria, Rodabe N.; Burton, Elizabeth M.; Woodman, Scott E.; Watowich, Stephanie; Diab, Adi; Patel, Sapna P.; Glitza, Isabella C.; Wong, Michael K.; Zhao, Li; Zhang, Jianhua; Ajami, Nadim J.; Petrosino, Joseph; Jenq, Robert R.; Davies, Michael A.; Gershenwald, Jeffrey E.; Futreal, P. Andrew; Sharma, Padmanee; Allison, James P.; Routy, Bertrand; Zitvogel, Laurence; Wargo, Jennifer A.
Source
Nature Medicine; 20210101, Issue: Preprints p1-10, 10p
Subject
Language
ISSN
10788956; 1546170X
Abstract
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 intestinalisin 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.