Transient Ablation of Regulatory T cells Improves Antitumor Immunity in Colitis-Associated Colon Cancer

Pastille, Eva; Bardini, Katrin; Fleissner, Diana; Adamczyk, Alexandra; Frede, Annika; Wadwa, Munisch; Smolinski, Dorthe von; Kasper, Stefan; Sparwasser, Tim; Gruber, Achim D.; Schüler, Martin; Sakaguchi, Shimon; Roers, Axel; Müller, Werner; Hansen, Wiebke; Buer, Jan; Westendorf, Astrid M.

doi:10.1158/0008-5472.can-13-3065

Cited by 87 publications

(103 citation statements)

References 46 publications

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“…To assess whether hypoxia is induced during CAC and whether low oxygen levels may impair an anti-tumour response, BALB/c mice were subjected to the azoxymethane (AOM)/dextran sulfate sodium (DSS) regimen, a well-established protocol for the induction of CAC [14, 16]. After injection of the procarcinogen AOM, the repeated administration of DSS via the drinking water induces a strong inflammatory response in the intestine.…”

Section: Resultsmentioning

confidence: 99%

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Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

Westendorf

Skibbe

Adamczyk

et al. 2017

Cell Physiol Biochem

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173

108

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Background/Aims: Hypoxia occurs in many pathological conditions, including inflammation and cancer. Within this context, hypoxia was shown to inhibit but also to promote T cell responses. Due to this controversial function, we aimed to explore whether an insufficient anti-tumour response during colitis-associated colon cancer could be ascribed to a hypoxic microenvironment. Methods: Colitis-associated colon cancer was induced in wildtype mice, and hypoxia as well as T cell immunity were analysed in the colonic tumour tissues. In addition, CD4⁺ effector T cells and regulatory T cells were cultured under normoxic and hypoxic conditions and examined regarding their phenotype and function. Results: We observed severe hypoxia in the colon of mice suffering from colitis-associated colon cancer that was accompanied by a reduced differentiation of CD4⁺ effector T cells and an enhanced number and suppressive activity of regulatory T cells. Complementary ex vivo and in vitro studies revealed that T cell stimulation under hypoxic conditions inhibited the differentiation, proliferation and IFN-γ production of T_H1 cells and enhanced the suppressive capacity of regulatory T cells. Moreover, we identified an active role for HIF-1α in the modulation of CD4⁺ T cell functions under hypoxic conditions. Conclusion: Our data indicate that oxygen availability can function as a local modulator of CD4⁺ T cell responses and thus influences tumour immune surveillance in inflammation-associated colon cancer.

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Section: Resultsmentioning

confidence: 99%

“…After injection of the procarcinogen AOM, the repeated administration of DSS via the drinking water induces a strong inflammatory response in the intestine. Mice lose as much as 10% of their initial body weight during the DSS cycles [16]. At week 12 after AOM/DSS treatment, we documented tumour development by endoscopy and histology (Fig.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

Westendorf

Skibbe

Adamczyk

et al. 2017

Cell Physiol Biochem

Self Cite

173

108

View full text Add to dashboard Cite

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“…Intratumoral Tregs are even more complex, since they have been reported to be associated with poor or favorable prognosis, not only in different cancer types, but also in the same cancer (94,95). It may reflect the heterogeneity of Treg subsets (96) in the tumor microenvironment or the selectivity of Treg markers (97).…”

Section: Other Parameters Impacting Cd8 + T Cells In Cancer Immunoedimentioning

confidence: 99%

From mice to humans: developments in cancer immunoediting

Teng¹,

Galon²,

Fridman³

et al. 2015

Journal of Clinical Investigation

295

219

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“…Decline in CD4 + T effector cell function with progressive tumor growth in HCC is related to increased Treg mediated suppression [3,4]. Even though, the suppressive role of Tregs during the inflammation is beneficial for maintenance of normal immune homeostasis, increase in the number of Tregs during tumor progression suppresses CD8 + T effector cell mediated anti-tumor immunity; hence creating a barrier to successful immunotherapy of cancer [5–7]. On the contrary, a paradox has been reported in colorectal cancer; while some studies concluded that high density of Tregs in the tumor microenvironment is associated with better prognosis, other studies reported their elevated numbers are associated with advanced stage tumors and poor overall survival [8].…”

Section: Immunosuppression By Tregsmentioning

confidence: 99%

High immunosuppressive burden in cancer patients: a major hurdle for cancer immunotherapy

Kalathil

Thanavala

2016

Cancer Immunol Immunother

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A bottleneck for immunotherapy of cancer is the immunosuppressive microenvironment in which the tumor cells are located. Regardless of the fact that large numbers of tumor-specific T cells can be generated in patients by active immunization or adoptive transfer, these T cells do not readily translate to tumor cell killing in vivo. The immune regulatory mechanism which prevents autoimmunity may be harnessed by tumor cells for the evasion of immune destruction. Regulatory T cells, myeloid-derived suppressor cells, inhibitory cytokines and immune checkpoint receptors are the major components of the immune system acting in concert to cause the subversion of anti-tumor immunity in the tumor microenvironment. This redundant immunosuppressive network may pose an impediment to efficacious immunotherapy, thus facilitating tumor progression. Cancer progression clearly documents the failure of immune control over relentless growth of tumor cells. Detailed knowledge of each of these factors responsible for creating an immunosuppressive shield to protect tumor cells from immune destruction is essential for the development of novel immune based therapeutic interventions of cancer. Multi-pronged targeted depletion of these suppressor cells may restore production of granzyme B by CD8+ T cells and increase the number of IFN-γ producing CD4+ T cells.

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Transient Ablation of Regulatory T cells Improves Antitumor Immunity in Colitis-Associated Colon Cancer

Abstract: Regulatory T cells (Treg) are supportive to cancer development in most tissues, but their role in colitisassociated colon cancer (CAC) remains unclear. In this study, we investigated the role of CD4

Cited by 87 publications

References 46 publications

Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

From mice to humans: developments in cancer immunoediting

High immunosuppressive burden in cancer patients: a major hurdle for cancer immunotherapy

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