Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients

  • Science. 2018 Jan 5;359(6371):97-103. doi: 10.1126/science.aan4236.
V Gopalakrishnan  1  2 C N Spencer  2  3 L Nezi  3 A Reuben  1 M C Andrews  1 T V Karpinets  3 P A Prieto  1 D Vicente  1 K Hoffman  4 S C Wei  5 A P Cogdill  1  5 L Zhao  3 C W Hudgens  6 D S Hutchinson  7 T Manzo  3 M Petaccia de Macedo  6 T Cotechini  8 T Kumar  3 W S Chen  9 S M Reddy  10 R Szczepaniak Sloane  1 J Galloway-Pena  11 H Jiang  1 P L Chen  9 E J Shpall  12 K Rezvani  12 A M Alousi  12 R F Chemaly  11 S Shelburne  3  11 L M Vence  5 P C Okhuysen  11 V B Jensen  13 A G Swennes  7 F McAllister  14 E Marcelo Riquelme Sanchez  14 Y Zhang  14 E Le Chatelier  15 L Zitvogel  16 N Pons  15 J L Austin-Breneman  1 L E Haydu  1 E M Burton  1 J M Gardner  1 E Sirmans  17 J Hu  18 A J Lazar  6  9 T Tsujikawa  8 A Diab  17 H Tawbi  17 I C Glitza  17 W J Hwu  17 S P Patel  17 S E Woodman  17 R N Amaria  17 M A Davies  17 J E Gershenwald  1 P Hwu  17 J E Lee  1 J Zhang  3 L M Coussens  8 Z A Cooper  1  3 P A Futreal  3 C R Daniel  4  2 N J Ajami  7 J F Petrosino  7 M T Tetzlaff  6  9 P Sharma  5  19 J P Allison  5 R R Jenq  3 J A Wargo  20  3
Affiliations
  • 1. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 2. Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX 77030, USA.
  • 3. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 4. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 5. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 6. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 7. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 8. Department of Cell, Developmental and Cell Biology, Oregon Health and Sciences University, Portland, OR 97239, USA.
  • 9. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 10. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 11. Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 12. Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 13. Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 14. Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 15. Centre de Recherche de Jouy-en-Josas, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas, France.
  • 16. Centre d'Investigation Clinique Biothérapie, Institut Gustave-Roussy, 94805 Villejuif Cedex, France.
  • 17. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 18. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 19. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 20. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. [email protected].
Abstract

Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human Cancer patients. Here we examined the oral and gut microbiome of Melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher Alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of Melanoma patients with immune checkpoint inhibitors.