Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma
Andreas Bonertz, Jürgen Weitz, Dong-Ho Kim Pietsch, Nuh N. Rahbari, Christoph Schlude, Yingzi Ge, Simone Juenger, Israel Vlodavsky, Khashayarsha Khazaie, Dirk Jaeger, Christoph Reissfelder, Dalibor Antolovic, Maximilian Aigner, Moritz Koch, Philipp Beckhove
Andreas Bonertz, Jürgen Weitz, Dong-Ho Kim Pietsch, Nuh N. Rahbari, Christoph Schlude, Yingzi Ge, Simone Juenger, Israel Vlodavsky, Khashayarsha Khazaie, Dirk Jaeger, Christoph Reissfelder, Dalibor Antolovic, Maximilian Aigner, Moritz Koch, Philipp Beckhove
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Research Article

Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma

Abstract

Spontaneous antitumor T cell responses in cancer patients are strongly controlled by Tregs, and increased numbers of tumor-infiltrating Tregs correlate with reduced survival. However, the tumor antigens recognized by Tregs in cancer patients and the impact of these cells on tumor-specific T cell responses have not been systematically characterized. Here we used a broad panel of long synthetic peptides of defined tumor antigens and normal tissue antigens to exploit a newly developed method to identify and compare ex vivo the antigen specificities of Tregs with those of effector/memory T cells in peripheral blood of colorectal cancer patients and healthy subjects. Tregs in tumor patients were highly specific for a distinct set of only a few tumor antigens, suggesting that Tregs exert T cell suppression in an antigen-selective manner. Tumor-specific effector T cells were detectable in the majority of colorectal cancer patients but not in healthy individuals. We detected differences in the repertoires of antigens recognized by Tregs and effector/memory T cells in the majority of colorectal cancer patients. In addition, only effector/memory T cell responses against antigens recognized by Tregs strongly increased after Treg depletion. The selection of antigens according to preexisting T cell responses may improve the efficacy of future immunotherapies for cancer and autoimmune disease.

Authors

Andreas Bonertz, Jürgen Weitz, Dong-Ho Kim Pietsch, Nuh N. Rahbari, Christoph Schlude, Yingzi Ge, Simone Juenger, Israel Vlodavsky, Khashayarsha Khazaie, Dirk Jaeger, Christoph Reissfelder, Dalibor Antolovic, Maximilian Aigner, Moritz Koch, Philipp Beckhove

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Figure 1

T cell responses against TAAs in CRC patients and healthy donors.

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T cell responses against TAAs in CRC patients and healthy donors. (A) Pr...
(A) Primary data from an exemplary IFN-γ ELISPOT assay. Peripheral blood T cells of 120 patients and 32 healthy donors were stimulated with polypeptides derived from negative control antigen (human IgG), normal self antigens, or the respective test tumor antigens. Data represent mean spot number of 3 wells per antigen ± SEM. **P < 0.05, spot numbers in test wells compared with pooled spot numbers of negative control antigen (2-tailed Student’s t test). TC, T cells. (B) Cumulative total IFN-γ spots from Treg-undepleted T cells for control antigen (IgG) in responding and nonresponding patients and responding and nonresponding TAAs. Mean ± SEM; *P < 0.05 (2-tailed Student’s t test); IgG, n = 21–28; TAAs, n = 29–127. (C) Primary data of an IFN-γ ELISPOT assay with CD45RO+ Tmems or CD45RO– naive T cells. Mean ± SEM; asterisks indicate significant differences between those groups that are connected by horizontal lines. *P < 0.05. (D) Frequency of TAA-specific T cells from responding CRC patients for single TAAs. Mean ± SEM; asterisks indicate significant differences between those groups that are connected by horizontal lines; *P < 0.05; **P < 0.01; n = 2–8. (E) Proportions of CRC patients and healthy donors among all individuals tested that exerted significant T cell reactivity against TAAs from autologous tumor or against polypeptides derived from the respective tumor antigens. Data represent the percentage of patients or healthy donors with TAA-specific T cells; n = 10–36. (F) Number of different TAAs recognized in individual responding patients; n = 25. (G) Frequency of TAA-specific T cells from individual CRC patients and healthy donors (HD). Mean ± SEM. ***P < 0.0001; n = 238–269.