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 4

SVY antigen in B.breve bacteria stimulates an immunogenic T cell response.

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SVY antigen in B.breve bacteria stimulates an immunogenic T cell respons...
(A) CD8+ T cells were isolated and expanded from Jackson and Taconic splenocytes with KbSVY aAPCS. On day 7, cells were harvested and stained for antigen specificity. Data represent 1 of 5 independent experiments. (B) CD8+ T cells were harvested and expanded as in A. Data show percentage of KbSVY+ CD8+ T cells. P value = 0.0025, measured by a 1-tailed, paired t test. N = 5. (C) Total cell numbers for CD8+ T cell enrichment and expansion with KbSVY aAPCs. P value = 0.0214, measured by 1-tailed, paired t test. N = 5. (D) Jackson and Taconic mouse CD8+ T cells stimulated as in A. On day 7, cells were harvested and stained with a titration of KbSVY. Results are reported as percentage of peptide-MHC positivity relative to that observed at 10 μg pMHC. Jackson (blue) and Taconic (red) peptide stains were compared at a given concentration. P value = 0.0071, measured by 2-way ANOVA and Bonferroni’s post hoc test for multiple comparisons. N = 3. (E and F) Taconic mice were immunized by intraperitoneal injection of αCD40 on day –8 and subcutaneous injection of KbSVY on day –7. (E) On day 0, control or immunized mice were injected intravenously with target and nontarget autologous splenocytes mixed at a 1:1 ratio. Spleens were harvested from mice on day 1, and the ratio of target to nontarget cells was analyzed. P < 0.0001 by 2-tailed, unpaired t test. N = 3 mice/group. (F) Taconic mice were sacrificed on day 1. Spleens and draining lymph nodes were harvested and stained for KbSVY specificity. P = 0.019 by 2-tailed, unpaired t test. N = 6 immunized, 3 not immunized. (G) Jackson and Taconic mice were cohoused for 7 days or separately housed with littermates. CD8+ T cells from splenocytes stimulated as in A and harvested and stained for antigen specificity on day 7. Antigen specificity measured by subtracting noncognate antigen reactivity. P value = 0.0014 by 1-tailed t test. N = 5 Taconic only; N = 8 cohoused animals. (H) Jackson and Taconic mice were either cohoused for 7 days or housed with their respective littermates. CD8+ T cells were isolated and enriched and expanded with KbOVA aAPCS and harvested and stained for antigen specificity on day 7. Antigen specificity was measured by subtracting the noncognate antigen specificity. No statistical difference seen by 1-tailed, unpaired t test. N = 4. All cells gated on live CD8+ cells. All data represent mean ± SEM.