CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer

Roux, Stéphan; Apétoh, Lionel; Chalmin, Fanny; Ladoire, Sylvain; Mignot, Grégoire; Puig, Pierre Emmanuel; Lauvau, Grégoire; Zitvogel, Laurence; Martin, François; Chauffert, Bruno; Yagita, Hideo; Solary, Éric; Ghiringhelli, François

doi:10.1172/jci35890

Cited by 58 publications

(38 citation statements)

References 64 publications

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“…In rodent models, we observed that administration of a low dose cyclophosphamide selectively decreases the number of circulating Treg in cancer-bearing animals and strongly enhances the tumor response to immunotherapy (Ghiringhelli et al, 2004;Taieb et al, 2006;Roux et al, 2008). These preclinical results were later confirmed by other investigators (Liu et al, 2007).…”

Section: Foxp3 þ Treg and Cancer Treatmentsupporting

confidence: 59%

Human FOXP3 and cancer

et al. 2010

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FOXP3 is a transcription factor necessary and sufficient for induction of the immunosuppressive functions in regulatory T lymphocytes. Its expression was first considered as specific of this cell type, but FOXP3 can also be transiently expressed in T-cell antigen receptoractivated human nonregulatory T cells. Recent data indicate that FOXP3 is also expressed by some nonlymphoid cells, in which it can repress various oncogenes that are restored following FOXP3 deletion or mutation. This review summarizes major advances in (1) the understanding of Foxp3 functions in human regulatory T cells, (2) the prognostic significance of Foxp3-expressing T cells in human malignancies and (3) the significance of Foxp3 expression in human tumor cells.

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Section: Foxp3 þ Treg and Cancer Treatmentsupporting

confidence: 59%

Human FOXP3 and cancer

et al. 2010

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“…Although we did not observe a major increase in CD11c + I-A/I-E + APC in tumor beds (Supplementary Figure 1), we cannot exclude the possibility that LTX-315 could boost the capacity of APC to increase their direct or indirect participation in anticancer immunosurveillance. 38,39 Third, the local immunotherapy should provide agonists for pattern recognition receptors (PRRs) to boost APC functions. Indeed, LTX-315 could provide the release of DAMPs (such as adenosine triphosphate).…”

Section: Discussionmentioning

confidence: 99%

The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade

et al. 2016

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Intratumoral immunotherapies aim at reducing local immunosuppression, as well as reinstating and enhancing systemic anticancer T-cell functions, without inducing side effects. LTX-315 is a first-in-class oncolytic peptide-based local immunotherapy that meets these criteria by inducing a type of malignant cell death that elicits anticancer immune responses. Here, we show that LTX-315 rapidly reprograms the tumor microenvironment by decreasing the local abundance of immunosuppressive Tregs and myeloid-derived suppressor cells and by increasing the frequency of polyfunctional T helper type 1/type 1 cytotoxic T cells with a concomitant increase in cytotoxic T-lymphocyte antigen-4 (CTLA4) and drop in PD-1 expression levels. Logically, in tumors that were resistant to intratumoral or systemic CTLA4 blockade, subsequent local inoculation of LTX-315 cured the animals or caused tumor regressions with abscopal effects. This synergistic interaction between CTLA4 blockade and LTX-315 was reduced upon blockade of the β-chain of the interleukin-2 receptor (CD122). This preclinical study provides a strong rationale for administering the oncolytic peptide LTX-315 to patients who are receiving treatment with the CTLA4 blocking antibody ipilimumab.

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“…9,85,86 Also, APCs that have carried out tolerogenic phagocytosis facilitate cancer progression by disrupting the cross-talk between CD4 + T cells and CTLs. More specifically, tolerogenic APCs present TAAs only to CTLs but not to CD4 + T cells, thereby causing sub-optimal CTL activation.…”

Section: Regulated Necrosismentioning

confidence: 99%

Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

et al. 2016

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Phagocytosis of dying cells is a major homeostatic process that represents the final stage of cell death in a tissue context. Under basal conditions, in a diseased tissue (such as cancer) or after treatment with cytotoxic therapies (such as anticancer therapies), phagocytosis has a major role in avoiding toxic accumulation of cellular corpses. Recognition and phagocytosis of dying cancer cells dictate the eventual immunological consequences (i.e., tolerogenic, inflammatory or immunogenic) depending on a series of factors, including the type of 'eat me' signals. Homeostatic clearance of dying cancer cells (i.e., tolerogenic phagocytosis) tends to facilitate pro-tumorigenic processes and actively suppress antitumour immunity. Conversely, cancer cells killed by immunogenic anticancer therapies may stimulate non-homeostatic clearance by antigen-presenting cells and drive cancer antigen-directed immunity. On the other hand, (a general) inflammatory clearance of dying cancer cells could have pro-tumorigenic or antitumorigenic consequences depending on the context. Interestingly, the immunosuppressive consequences that accompany tolerogenic phagocytosis can be reversed through immune-checkpoint therapies. In the present review, we discuss the pivotal role of phagocytosis in regulating responses to anticancer therapy. We give particular attention to the role of phagocytosis following treatment with immunogenic or immune-checkpoint therapies, the clinical prognostic and predictive significance of phagocytic signals for cancer patients and the therapeutic strategies that can be employed for direct targeting of phagocytic determinants.

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CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer

Cited by 58 publications

References 64 publications

Human FOXP3 and cancer

Human FOXP3 and cancer

The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade

Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

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