Tumor emergence is sensed by self-specific CD44hi memory Tregs that create a dominant tolerogenic environment for tumors in mice

Darrasse-Jèze, Guillaume; Bergot, Anne‐Sophie; Durgeau, Aurélie; Billiard, Fabienne; Salomon, Benoı̂t L.; Cohen, José L.; Bellier, Bertrand; Podsypanina, Katrina; Klatzmann, David

doi:10.1172/jci36628

Cited by 97 publications

(145 citation statements)

References 76 publications

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“…33 Several reports revealed that effector/memory Treg have the suppressive activity superior to that of naive Treg 23 and exhibit a high proliferation rate. 22 , 34 Moreover, it has been shown that this compartment contains a substantial proportion of self-specific T cells susceptible to recruitment and activation by tumor self-antigens. 22 , 35 Therefore, the infiltration of Panc02 tumors with effector/memory Treg cells may be largely responsible for the inability of the immune system to reject the tumor, suggesting a Treg depletion as a possible therapeutic strategy for the pancreatic cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

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Low‐dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer

Shevchenko

Karakhanova

Soltek

et al. 2013

Intl Journal of Cancer

152

122

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms with extremely poor prognosis and a low survival rate. Immunosuppressive cell populations, e.g. regulatory T cells (Treg), appear to be important in PDAC, contributing to patient's poor prognosis. Therefore, we investigated the PDAC microenvironment with a focus on conventional and regulatory T cells in view of their potential therapeutic importance. We found that tumors from the murine Panc02 orthotopic model of PDAC were infiltrated with high numbers of Treg. Remarkably, these cells exhibited the effector/memory phenotype, suggesting their enhanced suppressive activity and higher proliferation capacity. Although we observed a steady increase in transforming growth factor-b (TGF-b) levels in the tumors, treatment with a specific inhibitor of TGF-b receptor I kinase failed to abrogate Treg accumulation. A CCR4 antagonist did not affect Treg percentage in the tumor either. However, intense Treg cell division in the tumor microenvironment was demonstrated, suggesting local proliferation as a major mechanism of Treg accumulation in PDAC. Notably, this accumulation was reduced by low-dose gemcitabine administration, resulting in a modestly increased survival of PDAC mice. Our results provide an insight into mechanisms of immunosuppression in PDAC, suggesting an important role for proliferative expansion of effector/memory Treg. Low-dose gemcitabine therapy selectively depletes Treg, providing a basis for new modalities of PDAC therapy.Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms having extremely poor prognosis with a 5-year survival rate of <1% and a median survival of 6 months. Even after surgical intervention, the 5-year survival rate is at best 15% without adjuvant therapy or 25% with adjuvant chemotherapy. 1 In contrast to other malignancies, pancreatic cancer is highly resistant to chemotherapy and targeted therapy. The molecular mechanisms that determine treatment resistance are poorly understood.

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Section: Discussionmentioning

confidence: 99%

“…22 Therefore, we asked if Panc02 tumors could elicit effector T cell response and/or mobilization of memory cells. In spleens of tumor-bearing mice, we detected a significant expansion of the effector/effector memory cell compartment …”

Section: Dominance Of Effector/memory Cells In the Pdac Tumorsmentioning

confidence: 99%

Low‐dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer

Shevchenko

Karakhanova

Soltek

et al. 2013

Intl Journal of Cancer

152

122

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“…Although other types of suppressive cell have been identified, most regulatory T cells are characterized by expression of surface CD25 and by intracellular FOXP3, a transcription factor that mediates many of their inhibitory capabilities (Fontenot et al, 2005). It is unclear what proportion of Tregs react with specificity to tumour antigens (Wang et al, 2005), or whether they are recruited through the recognition of shared self-antigens that are co-expressed by tumour cells (Nishikawa et al, 2003;Darrasse-Jeze et al, 2009). Tregs can inhibit effector T-cell responses during both the induction (Darrasse-Jeze et al, 2009) and the effector stages (Huehn et al, 2004;Sarween et al, 2004) by a number of mechanisms, such as through direct ligation of CTLA-4 with CD80 or CD86 on effector T cells, by promoting the development of inhibitory DCs, or through the generation of inhibitory cytokines, transforming growth factor-b and IL10 (von Boehmer, 2005).…”

Section: Suppression By Regulatory T Cellsmentioning

confidence: 99%

Harnessing the immune response to treat cancer

et al. 2010

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It is well established that the immune system has the capacity to attack malignant cells. During malignant transformation cells acquire numerous molecular and biochemical changes that render them potentially vulnerable to immune cells. Yet it is self-evident that a growing tumour has managed to evade these host defence mechanisms. The exact ways in which the immune system interacts with tumour cells and how cancers are able to escape immunological eradication have only recently started to be fully elucidated. Understanding the relationship between the tumour and the anti-tumour immune response and how this can be altered with conventional treatments and immune-targeted therapies is crucial to developing new treatments for patients with cancer. In this review, focusing on the anti-tumour T-cell response, we summarize our understanding of how tumours, cancer treatments and the immune system interact, how tumours evade the immune response and how this process could be manipulated for the benefit of patients with cancer.

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“…Parce que ces derniers réagissent en permanence aux antigènes du soi exprimés par les cellules tumorales comme par les cellules normales et que leur réponse est donc de type « mémoire ». Les Treg sont ainsi mobilisés bien plus rapidement et fortement lors de l'apparition d'une tumeur que ne le sont les lymphocytes T effecteurs qui étaient au repos avant que la tumeur n'apparaisse [14]. Cet avantage crucial des Treg est perdu en cas de vaccination préventive par des TAA.…”

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“…Cet avantage crucial des Treg est perdu en cas de vaccination préventive par des TAA. Les T effecteurs mémoires apparaissent alors résistants à la suppression qu'induisent les Treg [14]. Les immunothérapies efficaces qui voient le jour aujourd'hui prennent en compte l'inhibition de la réponse régulatrice cellulaire soit en la bloquant, soit en générant des cellules mémoires résistantes à son inhibition.…”

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