TY - JOUR
T1 - Commensal bacteria stimulate antitumor responses via T cell cross-reactivity
AU - Bessell, Catherine A.
AU - Isser, Ariel
AU - Havel, Jonathan J.
AU - Lee, Sangyun
AU - Bell, David R.
AU - Hickey, John W.
AU - Chaisawangwong, Worarat
AU - Bieler, Joan Glick
AU - Srivastava, Raghvendra
AU - Kuo, Fengshen
AU - Purohit, Tanaya
AU - Zhou, Ruhong
AU - Chan, Timothy A.
AU - Schneck, Jonathan P.
N1 - Funding Information:
We would like to thank Jeffrey Weber and Binquan Luan for their various help with the modeling part of the work. We thank all members of the Chan lab for helpful discussions. We thank the Marie-Josée and Henry R. Kravis Center for Molecular Oncology for excellent suggestions. We also thank Memorial Sloan Kettering Cancer Center core laboratories, including Integrated Genomics Operations, Molecular Cytology, Cytogenetics, and Flow Cytometry cores. We thank the Sears lab for access to germ-free mice for experiments. We thank Eliot Sachsenmeier for his help. We thank the Johns Hopkins Bloomberg School of Public Health Bloomberg Flow Cytometry and Immunology Core and Dr. Hao Zhang. RZ acknowledges the support of the IBM Blue Gene Science Program (W1258591, W1464125, W1464164). This study was funded in part through the NIH/National Cancer Institute Cancer Center Support Grant P30 CA008748. We acknowledge funding sources, including Pershing Square Sohn Cancer Research grant (to TAC), the PaineWebber Chair (to TAC), Stand Up 2 Cancer (to TAC), NIH R01 CA205426 (to TAC), NIH R35 CA232097 (to TAC), the STARR Cancer Consortium (to TAC), and the Precision Immunotherapy Kidney Cancer Fund (to TAC, RJM). JWH thanks the NIH Cancer Nanotechnology Training Center at the Johns Hopkins Institute for NanoBioTechnology, the National Science Foundation Graduate Research Fellowship (DGE-1232825), and the ARCS Foundation for fellowship support. AI is supported by the National Science Foundation Graduate Research Fellowship. This work was funded by support from the NIH R01-CA108835 to JPS, R21-EB023411 to JPS, R33-CA229042 to JPS, and P41-EB028239 to JPS; a grant from AstraZeneca (to JPS); and a gift from the Troper Wojcicki Foundation (to JPS).
Funding Information:
cofounder of Gritstone Oncology and holds equity. TAC holds equity in An2H. TAC acknowledges grant funding from Bristol Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai. TAC has served as an advisor for Bristol Myers Squibb, Illumina, Eisai, and An2H. Under a licensing agreement between NexImmune and the Johns Hopkins University, JPS is entitled to shares of royalty received by the university on sales of artificial antigen-presenting cell products described in this article. He also owns NexImmune stock, which is subject to certain restrictions under university policy. JPS is a member of the company’s Scientific Advisory Board. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies. JPS acknowledges grant funding from AstraZeneca.
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/4/23
Y1 - 2020/4/23
N2 - Recent studies show gut microbiota modulate antitumor immune responses; one proposed mechanism is cross-reactivity between antigens expressed in commensal bacteria and neoepitopes. We found that T cells targeting an epitope called SVYRYYGL (SVY), expressed in the commensal bacterium Bifidobacterium breve (B. breve), cross-react with a model neoantigen, SIYRYYGL (SIY). Mice lacking B. breve had decreased SVY-reactive T cells compared with B. breve-colonized mice, and the T cell response was transferable by SVY immunization or by cohousing mice without Bifidobacterium with ones colonized with Bifidobacterium. Tumors expressing the model SIY neoantigen also grew faster in mice lacking B. breve compared with Bifidobacterium-colonized animals. B. breve colonization also shaped the SVY-reactive TCR repertoire. Finally, SVY-specific T cells recognized SIY-expressing melanomas in vivo and led to decreased tumor growth and extended survival. Our work demonstrates that commensal bacteria can stimulate antitumor immune responses via cross-reactivity and how bacterial antigens affect the T cell landscape.
AB - Recent studies show gut microbiota modulate antitumor immune responses; one proposed mechanism is cross-reactivity between antigens expressed in commensal bacteria and neoepitopes. We found that T cells targeting an epitope called SVYRYYGL (SVY), expressed in the commensal bacterium Bifidobacterium breve (B. breve), cross-react with a model neoantigen, SIYRYYGL (SIY). Mice lacking B. breve had decreased SVY-reactive T cells compared with B. breve-colonized mice, and the T cell response was transferable by SVY immunization or by cohousing mice without Bifidobacterium with ones colonized with Bifidobacterium. Tumors expressing the model SIY neoantigen also grew faster in mice lacking B. breve compared with Bifidobacterium-colonized animals. B. breve colonization also shaped the SVY-reactive TCR repertoire. Finally, SVY-specific T cells recognized SIY-expressing melanomas in vivo and led to decreased tumor growth and extended survival. Our work demonstrates that commensal bacteria can stimulate antitumor immune responses via cross-reactivity and how bacterial antigens affect the T cell landscape.
UR - http://www.scopus.com/inward/record.url?scp=85083947714&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85083947714&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.135597
DO - 10.1172/jci.insight.135597
M3 - Article
C2 - 32324171
AN - SCOPUS:85083947714
SN - 2379-3708
VL - 5
JO - JCI Insight
JF - JCI Insight
IS - 8
M1 - e135597
ER -