Commensal bacteria stimulate antitumor responses via T cell cross-reactivity
Catherine A. Bessell, Ariel Isser, Jonathan J. Havel, Sangyun Lee, David R. Bell, John W. Hickey, Worarat Chaisawangwong, Joan Glick Bieler, Raghvendra Srivastava, Fengshen Kuo, Tanaya Purohit, Ruhong Zhou, Timothy A. Chan, Jonathan P. Schneck
Catherine A. Bessell, Ariel Isser, Jonathan J. Havel, Sangyun Lee, David R. Bell, John W. Hickey, Worarat Chaisawangwong, Joan Glick Bieler, Raghvendra Srivastava, Fengshen Kuo, Tanaya Purohit, Ruhong Zhou, Timothy A. Chan, Jonathan P. Schneck
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Research Article Immunology Oncology

Commensal bacteria stimulate antitumor responses via T cell cross-reactivity

Abstract

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.

Authors

Catherine A. Bessell, Ariel Isser, Jonathan J. Havel, Sangyun Lee, David R. Bell, John W. Hickey, Worarat Chaisawangwong, Joan Glick Bieler, Raghvendra Srivastava, Fengshen Kuo, Tanaya Purohit, Ruhong Zhou, Timothy A. Chan, Jonathan P. Schneck

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Figure 7

Commensal bacteria epitope cross-reactivity mediates an antitumor response.

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Commensal bacteria epitope cross-reactivity mediates an antitumor respon...
(A) Jackson mice (n = 5 SVY ACT; n = 4 no treatment) were injected with 2 × 106 B16.SIY cells subcutaneously on day 0. CD8+ T cells were harvested from spleens of independent Jackson mice and stimulated with KbSVY/anti-CD28 nanoparticles. On day 8, 1.3 × 105 of the resultant KbSVY-specific CD8+ T cells were injected intravenously into the tumor-bearing mice. Tumor growth curves show SVY ACT treatment significantly delayed tumor growth as compared with no treatment. P value = 0.0136, measured by 2-way ANOVA with Bonferroni’s post hoc test for multiple comparisons. Additionally, KbSVY ACT significantly increased survival compared with the no treatment group. Significance was measured by the log-rank test. P value = 0.0015. (B) Jackson mice were injected with 2 × 106 B16.SIY cells subcutaneously on day 0 and treated on day 8 with 1.3 × 105 KbSVY-specific CD8+ T cells via intravenous injection. Tumors were harvested on day 24 and analyzed by flow cytometry for GFP expression. Orange and blue indicate SVY T cell–treated mice and red indicates untreated mice. (C). Jackson mice (n = 3 SIY ACT, and n = 3 no treatment) were injected with 2 × 106 B16.SIY cells subcutaneously on day 0. CD8+ T cells were harvested from spleens of independent Jackson mice and stimulated with KbSIY/anti-CD28 nanoparticles. On day 8, 1.3 × 105 of the resultant SIY-reactive T cells were injected intravenously into tumor-bearing mice. Tumor growth curves show SIY ACT treatment significantly delayed tumor growth as compared with no treatment. Significance was measured by 2-way ANOVA with Bonferroni’s post hoc test for multiple comparisons (P < 0.001). ACT also significantly extended survival. Significance was measured by the log-rank test. P value = 0.024. N = 3/group.