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phase separation behavior—all of which could
affecttheefficiencyofassembly( 32 – 34 ). Our
observations of enhanced RNA packaging and
replication are consistent with recent reports
that the Delta variant (containing N:R203M)
generates viral RNA levels elevated by a factor
of 1000 within patients ( 35 ). Our results pro-
vide a molecular basis to explain why the
SARS-CoV-2 Delta variant demonstrates im-
proved viral fitness.


REFERENCES AND NOTES



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ACKNOWLEDGMENTS
We thank P.-Y. Shi for providing the plasmids for SARS-CoV-2
reverse genetics. We would also like to acknowledge J. Hamilton
for advice and guidance and S. Wyman and B. Bach for sequencing
of infectious clones. We also thank S. Pillai and H. S. Sperbert
at Vitalant Research Institute (San Francisco, CA) for providing
the 293T-ACE2-TMPRSS2 cells used for pseudovirus entry
assays, the S. P. J. Whelan laboratory for providing Vero cells
overexpressing human TMPRSS2, O. Schwartz from Institut
Pasteur for providing A549 cells stably expressing ACE2
(A549-ACE2), and K.-K. Conzelmann for providing BSR-T7/5 cells.
Funding:This project was funded by a grant from the National
Institutes of Health (NIH; R21AI59666). J.A.D. is a Howard Hughes
Medical Institute investigator. A.M.S. acknowledges the support
of the Natural Sciences and Engineering Research Council of
Canada (NSERC PDF-533021-2019) and IPC support from the NIH
(F31 AI164671-01).Author contributions:Conceptualization:
A.M.S. and J.A.D. Investigation: A.M.S., T.Y.T., T.T., I.P.C., A.C.,
M.M.K., B.S., P.-Y.C., J.M.H., and K.M.S. Methodology: A.M.S.,
T.Y.T., T.T., J.A.D., and M.O. Supervision: J.A.D. and M.O.
Writing: A.M.S., T.Y.T., T.T., and J.A.D.Competing interests:
A.M.S. and J.A.D. are inventors on a patent application filed by
the Gladstone Institutes and the University of California that
covers the method and composition of SARS-CoV-2 VLP preparations
for RNA transduction and expression in cells. J.A.D. is a cofounder
of Caribou Biosciences, Editas Medicine, Scribe Therapeutics, Intellia


Therapeutics, and Mammoth Biosciences. J.A.D. is a scientific

advisory board member of Vertex, Caribou Biosciences, Intellia

Therapeutics, eFFECTOR Therapeutics, Scribe Therapeutics,

Mammoth Biosciences, Synthego, Algen Biotechnologies,

Felix Biosciences, The Column Group, and Inari. J.A.D. is a director

at Johnson & Johnson and Tempus and has research projects

sponsored by Biogen, Pfizer, AppleTree Partners, and Roche.Data

and materials availability:All data are available in the main paper

or the supplementary materials. Plasmids are available from

Addgene (addgene.org) or by request. This work is licensed under

a Creative Commons Attribution 4.0 International (CC BY 4.0)

license, which permits unrestricted use, distribution, and

reproduction in any medium, provided the original work is properly

cited. To view a copy of this license, visit https://creativecommons.

org/licenses/by/4.0/. This license does not apply to figures/

photos/artwork or other content included in the article that is

credited to a third party; obtain authorization from the rights

holder before using such material.

SUPPLEMENTARY MATERIALS

science.org/doi/10.1126/science.abl6184

Materials and Methods

Figs. S1 to S6

Tables S1 to S3

References

MDAR Reproducibility Checklist

26 July 2021; accepted 29 October 2021

Published online 4 November 2021

10.1126/science.abl6184

IMMUNOTHERAPY

Dietary fiber and probiotics influence the gut


microbiome and melanoma immunotherapy response


Christine N. Spencer^1 †‡, Jennifer L. McQuade^2 †, Vancheswaran Gopalakrishnan^1 †§,

John A. McCulloch^3 †, Marie Vetizou^3 †, Alexandria P. Cogdill1,4†¶, Md A. Wadud Khan^1 , Xiaotao Zhang^5 ,

Michael G. White^1 , Christine B. Peterson^6 , Matthew C. Wong^1 , Golnaz Morad^1 , Theresa Rodgers^2 ,

Jonathan H. Badger^3 , Beth A. Helmink^1 #, Miles C. Andrews1,7, Richard R. Rodrigues^8 , Andrey Morgun^9 ,

Young S. Kim^10 , Jason Roszik^2 , Kristi L. Hoffman^11 , Jiali Zheng^5 **, Yifan Zhou^4 , Yusra B. Medik^4 ,

Laura M. Kahn4,12, Sarah Johnson^1 , Courtney W. Hudgens^13 , Khalida Wani^13 , Pierre-Olivier Gaudreau^14 ,

Angela L. Harris^15 , Mohamed A. Jamal^16 , Erez N. Baruch^17 , Eva Perez-Guijarro^18 , Chi-Ping Day^18 ,

Glenn Merlino^18 , Barbara Pazdrak^2 , Brooke S. Lochmann^2 , Robert A. Szczepaniak-Sloane^1 ,

Reetakshi Arora^1 , Jaime Anderson^2 , Chrystia M. Zobniw^2 , Eliza Posada^2 , Elizabeth Sirmans^2 ,

Julie Simon^1 , Lauren E. Haydu^1 , Elizabeth M. Burton^1 , Linghua Wang^16 , Minghao Dang^16 ,

Karen Clise-Dwyer19,20, Sarah Schneider^19 , Thomas Chapman^1 , Nana-Ama A. S. Anang^4 ,

Sheila Duncan^1 , Joseph Toker21,22, Jared C. Malke^1 , Isabella C. Glitza^2 , Rodabe N. Amaria^2 ,

Hussein A. Tawbi^2 , Adi Diab^2 , Michael K. Wong^2 , Sapna P. Patel^2 , Scott E. Woodman^2 ,

Michael A. Davies^2 , Merrick I. Ross^1 , Jeffrey E. Gershenwald^1 , Jeffrey E. Lee^1 , Patrick Hwu^2 ††,

Vanessa Jensen^23 , Yardena Samuels^24 , Ravid Straussman^24 , Nadim J. Ajami^16 , Kelly C. Nelson^25 ,

Luigi Nezi^26 , Joseph F. Petrosino^11 , P. Andrew Futreal^16 , Alexander J. Lazar12,16,27, Jianhua Hu^28 ,

Robert R. Jenq16,29, Michael T. Tetzlaff^30 , Yan Yan^31 , Wendy S. Garrett^32 , Curtis Huttenhower31,33,34,35,

Padmanee Sharma4,36,37, Stephanie S. Watowich^4 , James P. Allison4,37, Lorenzo Cohen^38 ‡‡,

Giorgio Trinchieri^3 *‡‡, Carrie R. Daniel^5 *‡‡, Jennifer A. Wargo1,16*‡‡

Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the

effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota

profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and

performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved

progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients

with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models,

which demonstrated impaired treatment response to anti–programmed cell death 1 (anti–PD-1)–based

therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-g–positive

cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for patients

receiving ICB for cancer.

T


reatment with immune checkpoint block-

ade (ICB) has revolutionized cancer ther-

apy ( 1 ), and the influence of the gut

microbiome on therapeutic response has

now been demonstrated in numerous hu-

mancohortsandinpreclinicalmodels( 2 – 7 ).

The human gut microbiome is itself shaped

by a wide variety of environmental exposures,

including diet ( 8 , 9 ) and medication use ( 10 – 13 ),

with host genetics accounting for <10% of varia-

tion ( 14 ). However, whether factors such as

dietary fiber intake and the use of commercially

available probiotics affect immunotherapy re-

sponses in cancer patients remains unclear.

To help address this, we profiled the gut

(fecal) microbiome and assessed clinicopatho-

logic features and outcomes in a large cohort

of melanoma patients (n=438;Fig.1Aand

fig. S1). The majority of these patients were

receiving systemic therapy for metastatic

melanoma (n= 321), and responses to treat-

ment were assessed with radiographic imaging

1632 24 DECEMBER 2021•VOL 374 ISSUE 6575 science.orgSCIENCE


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