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

V. Gopalakrishnan; C. N. Spencer; L. Nezi; A. Reuben; M. C. Andrews; T. V. Karpinets; P. A. Prieto; D. Vicente; K. Hoffman; S. C. Wei; A. P. Cogdill; L. Zhao; C. W. Hudgens; D. S. Hutchinson; T. Manzo; M. Petaccia De Macedo; T. Cotechini; T. Kumar; W. S. Chen; S. M. Reddy; R. Szczepaniak Sloane; J. Galloway-Pena; H. Jiang; P. L. Chen; E. J. Shpall; K. Rezvani; A. M. Alousi; R. F. Chemaly; S. Shelburne; L. M. Vence; P. C. Okhuysen; V. B. Jensen; A. G. Swennes; F. McAllister; E. Marcelo Riquelme Sanchez; Y. Zhang; E. Le Chatelier; L. Zitvogel; N. Pons; J. L. Austin-Breneman; L. E. Haydu; E. M. Burton; J. M. Gardner; E. Sirmans; J. Hu; A. J. Lazar; T. Tsujikawa; A. Diab; H. Tawbi; I. C. Glitza; W. J. Hwu; S. P. Patel; S. E. Woodman; R. N. Amaria; M. A. Davies; J. E. Gershenwald; P. Hwu; J. E. Lee; J. Zhang; L. M. Coussens; Z. A. Cooper; P. A. Futreal; C. R. Daniel; N. J. Ajami; J. F. Petrosino; M. T. Tetzlaff; P. Sharma; J. P. Allison; R. R. Jenq; J. A. Wargo

doi:10.1126/science.aan4236

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

V. Gopalakrishnan, C. N. Spencer, L. Nezi, A. Reuben, M. C. Andrews, T. V. Karpinets, P. A. Prieto, D. Vicente, K. Hoffman, S. C. Wei, A. P. Cogdill, L. Zhao, C. W. Hudgens, D. S. Hutchinson, T. Manzo, M. Petaccia De Macedo, T. Cotechini, T. Kumar, W. S. Chen, S. M. ReddyR. Szczepaniak Sloane, J. Galloway-Pena, H. Jiang, P. L. Chen, E. J. Shpall, K. Rezvani, A. M. Alousi, R. F. Chemaly, S. Shelburne, L. M. Vence, P. C. Okhuysen, V. B. Jensen, A. G. Swennes, F. McAllister, E. Marcelo Riquelme Sanchez, Y. Zhang, E. Le Chatelier, L. Zitvogel, N. Pons, J. L. Austin-Breneman, L. E. Haydu, E. M. Burton, J. M. Gardner, E. Sirmans, J. Hu, A. J. Lazar, T. Tsujikawa, A. Diab, H. Tawbi, I. C. Glitza, W. J. Hwu, S. P. Patel, S. E. Woodman, R. N. Amaria, M. A. Davies, J. E. Gershenwald, P. Hwu, J. E. Lee, J. Zhang, L. M. Coussens, Z. A. Cooper, P. A. Futreal, C. R. Daniel, N. J. Ajami, J. F. Petrosino, M. T. Tetzlaff, P. Sharma, J. P. Allison, R. R. Jenq, J. A. Wargo

Research output: Contribution to journal › Article › peer-review

3136 Citations (Scopus)

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.

Original language	English
Pages (from-to)	97-103
Number of pages	7
Journal	Science
Volume	359
Issue number	6371
DOIs	https://doi.org/10.1126/science.aan4236
Publication status	Published - 5 Jan 2018

Access to Document

10.1126/science.aan4236

Cite this

Gopalakrishnan, V., Spencer, C. N., Nezi, L., Reuben, A., Andrews, M. C., Karpinets, T. V., Prieto, P. A., Vicente, D., Hoffman, K., Wei, S. C., Cogdill, A. P., Zhao, L., Hudgens, C. W., Hutchinson, D. S., Manzo, T., Petaccia De Macedo, M., Cotechini, T., Kumar, T., Chen, W. S., ... Wargo, J. A. (2018). Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science, 359(6371), 97-103. https://doi.org/10.1126/science.aan4236

@article{4a7c8c82a1f24c1691d30a051e487950,

title = "Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients",

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.",

author = "V. Gopalakrishnan and Spencer, {C. N.} and L. Nezi and A. Reuben and Andrews, {M. C.} and Karpinets, {T. V.} and Prieto, {P. A.} and D. Vicente and K. Hoffman and Wei, {S. C.} and Cogdill, {A. P.} and L. Zhao and Hudgens, {C. W.} and Hutchinson, {D. S.} and T. Manzo and {Petaccia De Macedo}, M. and T. Cotechini and T. Kumar and Chen, {W. S.} and Reddy, {S. M.} and {Szczepaniak Sloane}, R. and J. Galloway-Pena and H. Jiang and Chen, {P. L.} and Shpall, {E. J.} and K. Rezvani and Alousi, {A. M.} and Chemaly, {R. F.} and S. Shelburne and Vence, {L. M.} and Okhuysen, {P. C.} and Jensen, {V. B.} and Swennes, {A. G.} and F. McAllister and {Marcelo Riquelme Sanchez}, E. and Y. Zhang and {Le Chatelier}, E. and L. Zitvogel and N. Pons and Austin-Breneman, {J. L.} and Haydu, {L. E.} and Burton, {E. M.} and Gardner, {J. M.} and E. Sirmans and J. Hu and Lazar, {A. J.} and T. Tsujikawa and A. Diab and H. Tawbi and Glitza, {I. C.} and Hwu, {W. J.} and Patel, {S. P.} and Woodman, {S. E.} and Amaria, {R. N.} and Davies, {M. A.} and Gershenwald, {J. E.} and P. Hwu and Lee, {J. E.} and J. Zhang and Coussens, {L. M.} and Cooper, {Z. A.} and Futreal, {P. A.} and Daniel, {C. R.} and Ajami, {N. J.} and Petrosino, {J. F.} and Tetzlaff, {M. T.} and P. Sharma and Allison, {J. P.} and Jenq, {R. R.} and Wargo, {J. A.}",

note = "Funding Information: The data reported in this paper are tabulated in the main text and supplementary materials. The authors wish to acknowledge all patients and families affected by melanoma. J.A.W. is supported by the Binational Science Foundation, the Melanoma Research Alliance, Stand Up To Cancer, an MD Anderson Cancer Center Multidisciplinary Research Program Grant, and MD Anderson Cancer Center{\textquoteright}s Melanoma Moon Shots Program. This project was supported by the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center{\textquoteright}s Melanoma Moon Shots program. J.A.W., P.S., and J.P.A. are members of the Parker Institute for Cancer Immunotherapy at MD Anderson Cancer Center. A.R. is supported by the Kimberley Clarke Foundation Award for Scientific Achievement provided by the Odyssey Fellowship program at The University of Texas MD Anderson Cancer Center. K.H. is supported by the National Cancer Institute (NCI) of NIH under award numbers CA016672 (principal investigator R. DePinho) and R25CA057730 (principal investigator S. Chang). J.E.L. is supported by philanthropic contributions to the University of Texas MD Anderson Cancer Center{\textquoteright}s Melanoma Moon Shots Program, The University of Texas MD Anderson Cancer Center{\textquoteright}s Various Donors Melanoma and Skin Cancers Priority Program Fund, the Miriam and Jim Mulva Research Fund, the McCarthy Skin Cancer Research Fund, and the Marit Peterson Fund for Melanoma Research. The authors acknowledge the Miriam and Sheldon G. Adelson Medical Research Foundation for their support of MD Anderson Cancer Center{\textquoteright}s Biospecimen Collection team. L.M.C. acknowledges a Stand Up To Cancer– Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant, support from the NCI of NIH, and the Brenden-Colson Center for Pancreatic Health. T.T. acknowledges the Oregon Clinical and Translational Research Institute from the National Center for Advancing Translational Sciences at the NIH (NIH #UL1TR000128). J.A.W. acknowledges C. Diaz for administrative support. Fecal, oral and murine 16S, and fecal WGS sequencing data are available from the European Nucelotide Archive under accession numbers PRJEB22894, PRJEB22874, PRJEB22895, and PRJEB22893, respectively. Human WGS sequencing data are available from the European Genome-phenome Archive under accession number EGAS00001002698. J.A.W. and V.G. are inventors on a U.S. patent application (PCT/US17/53717) submitted by The University of Texas MD Anderson Cancer Center that covers methods to enhance checkpoint blockade therapy by the microbiome. T.T. and L.M.C. are inventors on a World Intellectual Property Organization patent (WO 2017/087847) held by Oregon Health and Science University that covers the multiplex technology. M.A.D. is an advisory board member for Bristol-Myers Squibb, Novartis, GlaxoSmithKline, Roche/Genentech, Sanofi-Aventis, and Vaccinex and has received funding from GlaxoSmithKline, Roche/Genentech, Merck, AstraZeneca, and Sanofi-Aventis. A.J.L. is a consultant for MedImmune, Bristol-Myers Squibb, Novartis, and Merck and has received research support from AstraZeneca/MedImmune. Z.A.C. is an employee of MedImmune and owns stock or options in AstraZeneca. J.E.G. is on the advisory board of Merck and receives royalties from Mercator Therapeutics. S.P.P. has honoraria from Speaker{\textquoteright}s bureau of Dava Oncology, Merck, and Bristol-Myers Squibb and is an advisory board member for Amgen and Roche/Genentech. P.H. serves on the advisory board of Lion Biotechnologies and Immatics US. R.N.A. has received research support from Merck, Novartis, and Bristol-Myers Squibb. P.S. is a consultant for Bristol-Myers Squibb, Jounce Therapeutics, Helsinn, and GlaxoSmithKline and is also a stockholder from Jounce Therapeutics. J.P.A. is a consultant and stockholder for Jounce Therapeutics, receives royalties from Bristol-Myers Squibb, and has intellectual property with Bristol-Myers Squibb and Merck. J.A.W. has received honoraria from Speakers{\textquoteright} bureau of Dava Oncology, Bristol-Myers Squibb, and Illumina and is an advisory board member for GlaxoSmithKline, Novartis, and Roche/ Genentech. The other authors declare no competing interests.",

year = "2018",

month = jan,

day = "5",

doi = "10.1126/science.aan4236",

language = "English",

volume = "359",

pages = "97--103",

journal = "Science",

issn = "0036-8075",

number = "6371",

}

Gopalakrishnan, V, Spencer, CN, Nezi, L, Reuben, A, Andrews, MC, Karpinets, TV, Prieto, PA, Vicente, D, Hoffman, K, Wei, SC, Cogdill, AP, Zhao, L, Hudgens, CW, Hutchinson, DS, Manzo, T, Petaccia De Macedo, M, Cotechini, T, Kumar, T, Chen, WS, Reddy, SM, Szczepaniak Sloane, R, Galloway-Pena, J, Jiang, H, Chen, PL, Shpall, EJ, Rezvani, K, Alousi, AM, Chemaly, RF, Shelburne, S, Vence, LM, Okhuysen, PC, Jensen, VB, Swennes, AG, McAllister, F, Marcelo Riquelme Sanchez, E, Zhang, Y, Le Chatelier, E, Zitvogel, L, Pons, N, Austin-Breneman, JL, Haydu, LE, Burton, EM, Gardner, JM, Sirmans, E, Hu, J, Lazar, AJ, Tsujikawa, T, Diab, A, Tawbi, H, Glitza, IC, Hwu, WJ, Patel, SP, Woodman, SE, Amaria, RN, Davies, MA, Gershenwald, JE, Hwu, P, Lee, JE, Zhang, J, Coussens, LM, Cooper, ZA, Futreal, PA, Daniel, CR, Ajami, NJ, Petrosino, JF, Tetzlaff, MT, Sharma, P, Allison, JP, Jenq, RR & Wargo, JA 2018, 'Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients', Science, vol. 359, no. 6371, pp. 97-103. https://doi.org/10.1126/science.aan4236

TY - JOUR

T1 - Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients

AU - Gopalakrishnan, V.

AU - Spencer, C. N.

AU - Nezi, L.

AU - Reuben, A.

AU - Andrews, M. C.

AU - Karpinets, T. V.

AU - Prieto, P. A.

AU - Vicente, D.

AU - Hoffman, K.

AU - Wei, S. C.

AU - Cogdill, A. P.

AU - Zhao, L.

AU - Hudgens, C. W.

AU - Hutchinson, D. S.

AU - Manzo, T.

AU - Petaccia De Macedo, M.

AU - Cotechini, T.

AU - Kumar, T.

AU - Chen, W. S.

AU - Reddy, S. M.

AU - Szczepaniak Sloane, R.

AU - Galloway-Pena, J.

AU - Jiang, H.

AU - Chen, P. L.

AU - Shpall, E. J.

AU - Rezvani, K.

AU - Alousi, A. M.

AU - Chemaly, R. F.

AU - Shelburne, S.

AU - Vence, L. M.

AU - Okhuysen, P. C.

AU - Jensen, V. B.

AU - Swennes, A. G.

AU - McAllister, F.

AU - Marcelo Riquelme Sanchez, E.

AU - Zhang, Y.

AU - Le Chatelier, E.

AU - Zitvogel, L.

AU - Pons, N.

AU - Austin-Breneman, J. L.

AU - Haydu, L. E.

AU - Burton, E. M.

AU - Gardner, J. M.

AU - Sirmans, E.

AU - Hu, J.

AU - Lazar, A. J.

AU - Tsujikawa, T.

AU - Diab, A.

AU - Tawbi, H.

AU - Glitza, I. C.

AU - Hwu, W. J.

AU - Patel, S. P.

AU - Woodman, S. E.

AU - Amaria, R. N.

AU - Davies, M. A.

AU - Gershenwald, J. E.

AU - Hwu, P.

AU - Lee, J. E.

AU - Zhang, J.

AU - Coussens, L. M.

AU - Cooper, Z. A.

AU - Futreal, P. A.

AU - Daniel, C. R.

AU - Ajami, N. J.

AU - Petrosino, J. F.

AU - Tetzlaff, M. T.

AU - Sharma, P.

AU - Allison, J. P.

AU - Jenq, R. R.

AU - Wargo, J. A.

N1 - Funding Information: The data reported in this paper are tabulated in the main text and supplementary materials. The authors wish to acknowledge all patients and families affected by melanoma. J.A.W. is supported by the Binational Science Foundation, the Melanoma Research Alliance, Stand Up To Cancer, an MD Anderson Cancer Center Multidisciplinary Research Program Grant, and MD Anderson Cancer Center’s Melanoma Moon Shots Program. This project was supported by the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center’s Melanoma Moon Shots program. J.A.W., P.S., and J.P.A. are members of the Parker Institute for Cancer Immunotherapy at MD Anderson Cancer Center. A.R. is supported by the Kimberley Clarke Foundation Award for Scientific Achievement provided by the Odyssey Fellowship program at The University of Texas MD Anderson Cancer Center. K.H. is supported by the National Cancer Institute (NCI) of NIH under award numbers CA016672 (principal investigator R. DePinho) and R25CA057730 (principal investigator S. Chang). J.E.L. is supported by philanthropic contributions to the University of Texas MD Anderson Cancer Center’s Melanoma Moon Shots Program, The University of Texas MD Anderson Cancer Center’s Various Donors Melanoma and Skin Cancers Priority Program Fund, the Miriam and Jim Mulva Research Fund, the McCarthy Skin Cancer Research Fund, and the Marit Peterson Fund for Melanoma Research. The authors acknowledge the Miriam and Sheldon G. Adelson Medical Research Foundation for their support of MD Anderson Cancer Center’s Biospecimen Collection team. L.M.C. acknowledges a Stand Up To Cancer– Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant, support from the NCI of NIH, and the Brenden-Colson Center for Pancreatic Health. T.T. acknowledges the Oregon Clinical and Translational Research Institute from the National Center for Advancing Translational Sciences at the NIH (NIH #UL1TR000128). J.A.W. acknowledges C. Diaz for administrative support. Fecal, oral and murine 16S, and fecal WGS sequencing data are available from the European Nucelotide Archive under accession numbers PRJEB22894, PRJEB22874, PRJEB22895, and PRJEB22893, respectively. Human WGS sequencing data are available from the European Genome-phenome Archive under accession number EGAS00001002698. J.A.W. and V.G. are inventors on a U.S. patent application (PCT/US17/53717) submitted by The University of Texas MD Anderson Cancer Center that covers methods to enhance checkpoint blockade therapy by the microbiome. T.T. and L.M.C. are inventors on a World Intellectual Property Organization patent (WO 2017/087847) held by Oregon Health and Science University that covers the multiplex technology. M.A.D. is an advisory board member for Bristol-Myers Squibb, Novartis, GlaxoSmithKline, Roche/Genentech, Sanofi-Aventis, and Vaccinex and has received funding from GlaxoSmithKline, Roche/Genentech, Merck, AstraZeneca, and Sanofi-Aventis. A.J.L. is a consultant for MedImmune, Bristol-Myers Squibb, Novartis, and Merck and has received research support from AstraZeneca/MedImmune. Z.A.C. is an employee of MedImmune and owns stock or options in AstraZeneca. J.E.G. is on the advisory board of Merck and receives royalties from Mercator Therapeutics. S.P.P. has honoraria from Speaker’s bureau of Dava Oncology, Merck, and Bristol-Myers Squibb and is an advisory board member for Amgen and Roche/Genentech. P.H. serves on the advisory board of Lion Biotechnologies and Immatics US. R.N.A. has received research support from Merck, Novartis, and Bristol-Myers Squibb. P.S. is a consultant for Bristol-Myers Squibb, Jounce Therapeutics, Helsinn, and GlaxoSmithKline and is also a stockholder from Jounce Therapeutics. J.P.A. is a consultant and stockholder for Jounce Therapeutics, receives royalties from Bristol-Myers Squibb, and has intellectual property with Bristol-Myers Squibb and Merck. J.A.W. has received honoraria from Speakers’ bureau of Dava Oncology, Bristol-Myers Squibb, and Illumina and is an advisory board member for GlaxoSmithKline, Novartis, and Roche/ Genentech. The other authors declare no competing interests.

PY - 2018/1/5

Y1 - 2018/1/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85033587326&partnerID=8YFLogxK

U2 - 10.1126/science.aan4236

DO - 10.1126/science.aan4236

M3 - Article

C2 - 29097493

AN - SCOPUS:85033587326

SN - 0036-8075

VL - 359

SP - 97

EP - 103

JO - Science

JF - Science

IS - 6371

ER -

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

Abstract

Access to Document

Other files and links

Cite this