Contribution of IL-17–producing γδ T cells to the efficacy of anticancer chemotherapy

Ma, Yuting; Aymeric, Laetitia; Locher, Clara; Mattarollo, Stephen R.; Delahaye, Nicolas; Pereira, Pablo; Boucontet, Laurent; Apétoh, Lionel; Ghiringhelli, François; Casares, Noëlia; Lasarte, Juan José; Matsuzaki, Goro; Ikuta, Koichi; Ryffel, Bernard; Benlagha, Kamel; Tesnière, Antoine; Ibrahim, Nicolas; Déchanet‐Merville, Julie; Chaput, Nathalie; Smyth, Mark J.; Kroemer, Guido; Zitvogel, Laurence

doi:10.1084/jem.20100269

Cited by 309 publications

(275 citation statements)

References 56 publications

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“…This expansion of OVA-specific T cells reflects a general increase in the frequency of Th1 and Tc1 cells post chemotherapy. 16,17 In sharp contrast, doxorubicin depleted intratumoral B cells by more than 70% (Figure 1c). Moreover, a single systemic injection of cyclophosphamide reduced the number of splenic B cells, while it increased the frequency of CTL in the spleen (Supplementary Figures 1A-C).…”

Section: Resultsmentioning

confidence: 95%

“…To evaluate the possible anticancer immune responses mediated by B cells, we determined the absolute numbers of CD19 þ B220 þ B lymphocytes in the CD45 þ leukocytic fraction from tumors established subcutaneously for 18 days and harvested at day 8 post chemotherapy with anthracyclines, following previously established experimental settings. 16,17 MCA205 OVA, a methylcholanthrene-induced sarcoma cell line genetically modified to express the candidate tumor antigen OVA, was injected under the skin of histocompatible C57Bl/6 mice, and the developing cancers were treated by intratumoral injections of anthracyclines (doxorubicin). CD45.2 OVA (SIIN-FEKL)-specific H2-K b -restricted TCR transgenic CD8 þ T cells (CTL) that were adoptively transferred into CD45.1 congenic mice on the first day post chemotherapy proliferated and accumulated in tumor beds (Figures 1a and b).…”

Section: Resultsmentioning

confidence: 99%

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Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

et al. 2013

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Immunogenic cell death induced by cytotoxic compounds contributes to the success of selected chemotherapies by eliciting a protective anticancer immune response, which is mediated by CD4 þ and CD8 þ T cells producing interferon-c. In many instances, cancer progression is associated with high titers of tumor-specific antibodies, which become detectable in the serum, but whose functional relevance is elusive. Here, we explored the role of humoral immune responses in the anticancer efficacy of anthracyclines. Chemotherapy reduced the number of tumor-infiltrating B cells, and failed to promote humoral responses against immunodominant tumor antigens. Although anthracycline-based anticancer chemotherapies failed in T cell-deficient mice, they successfully reduced the growth of cancers developing in mice lacking B lymphocytes (due to the injection of a B-celldepleting anti-CD20 antibody), immunoglobulins (Igs) or Ig receptors (Fc receptor) due to genetic manipulations. These results suggest that the humoral arm of antitumor immunity is dispensable for the immune-dependent therapeutic effect of anthracyclines against mouse sarcoma. In addition, we show here that the titers of IgA and IgG antibodies directed against an autoantigen appearing at the cell surface of tumor cells post chemotherapy (calreticulin, CRT) did not significantly increase in patients treated with anthracyclines, and that anti-CRT antibodies had no prognostic or predictive significance. Collectively, our data indicate that humoral anticancer immune responses differ from cellular responses in, thus far, that they do not contribute to the success of anthracycline-mediated anticancer therapies in human breast cancers and mouse sarcomas.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

et al. 2013

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“…The role of IL-17 + γδ T lymphocytes (and of IL-17) in infection, tumor immunity, and autoimmunity has been reported, and it is still controversial [50,[58][59][60][61][62][63]. A clear involvement of IL-17 + γδ T lymphocytes in autoimmunity has been evidenced in experimental arthritis and autoimmune encephalomyelitis, in which these cells have been shown to amplify CD4 + Th17 cell responses, to suppress Foxp3 + Treg cells, and to contribute to the development of the response [48,[62][63][64].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is possible that the relevance of CCL25 in the context of allergic responses is correlated to IL-17 production in the allergic site. Whether this phenomenon contributes to the enhancement or regulation of allergy is still unclear, since contrasting roles for IL-17 have been described [54][55][56][57].The role of IL-17 + γδ T lymphocytes (and of IL-17) in infection, tumor immunity, and autoimmunity has been reported, and it is still controversial [50,[58][59][60][61][62][63]. A clear involvement of IL-17 + γδ T lymphocytes in autoimmunity has been evidenced in experimental arthritis and autoimmune encephalomyelitis, in which these cells .…”

mentioning

confidence: 99%

CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

Costa¹,

Bornstein²,

Candéa³

et al. 2012

Eur J Immunol

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Herein, we provide evidence that during allergic inflammation, CCL25 induces the selective migration of IL-17 + γδ T cells mediated by α 4 β 7 integrin. Intrapleural injection of CCL25 into ovalbumin (OVA)-immunized C57BL/6 mice triggered the accumulation of γδ T lymphocytes expressing CCR9 (CCL25 receptor) and α 4 β 7 integrin in the pleura, but failed to attract αβ T lymphocytes. CCL25 attracted CCR6 + γδ T cells producing IL-17 (but not IFN-γ or IL-4). OVA challenge triggered increased production of CCL25 followed by the accumulation of CCR9 + , α 4 β 7 + , and CCR6 + /IL-17 + γδ T cells into the pleural cavities of OVA-immunized mice, which was inhibited by the in vivo neutralization of CCL25. The in vivo blockade of α 4 β 7 integrin also inhibited the migration of IL-17 + γδ T lymphocytes (but not of αβ T lymphocytes) into mouse pleura after OVA challenge, suggesting that the CCL25/α 4 β 7 integrin pathway is selective for γδ T cells. In addition, α 4 β 7 integrin blockade impaired the in vitro transmigration of γδ T cells across endothelium (which expresses α 4 β 7 ligands VCAM-1 and MadCAM-1), which was induced by CCL25 and by cell-free pleural washes recovered from OVA-challenged mice. Our results reveal that during an allergic reaction, CCL25 drives IL-17 + γδ T-cell mobilization to inflamed tissue via α 4 β 7 integrin and modulates IL-17 levels. Keywords: Adhesion molecules IntroductionLymphocytes bearing the γδ T-cell receptor (TCR) comprise a minor T-lymphocyte subset in blood and secondary lymphoid tissues and are preferentially localized in epithelial and mucosal tissues [1,2]. This unique subset of lymphocytes can provide rapid tissue-specific immune responses, without the requirement of antiCorrespondence: Dr. Carmen Penido e-mail: cpenido@far.fiocruz.br gen presentation or clonal expansion, and is able to produce a large repertory of Th1-, Th2-, and Th17-associated cytokines [2][3][4][5][6]. These characteristics make γδ T cells a crucial first line of defense during infection, tissue damage, or stress.γδ T cells have been shown to migrate into the airways during allergic inflammation highly controlled by a chemotactic gradient of chemokines produced in tissue [5,[7][8][9][10][11]. We have previously demonstrated that allergen-induced γδ T-cell accumulation is * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2012. 42: 1250-1260 Immunomodulation 1251 paralleled with a marked production of chemokines in the tissue, including CCL25/TECK [11]. CCL25 is mostly described as a homeostatic chemokine that plays a major role in T-cell development in the thymus and in intraepithelial lymphocytes (IELs) homing into small intestine mucosa [12]. Recent data have provided evidence that CCL25 production increases during inflammatory processes that take place at nonmucosal tissues, such as autoimmune arthritis, atherosclerosis, and allergy [11,13,14]. Moreover, we and others have shown that γδ T lymphocytes migrate in vitro toward CCL25, via its counterpart receptor CCR9 [11,...

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“…5-FU-exposed MDSCs stimulate CD4 + T cells to express IL17 via IL1β; although, the mechanism by which IL17-producing CD4 + T cells (otherwise known as Th17 cells) counteract the anti-cancer efficacy of 5-FU is unclear. By contrast, IL17 is required for therapeutic efficacy of doxorubicin in a subcutaneous sarcoma model, and γδ T cells, not CD4 + T cells, are the source of IL17 in this scenario [68]. In MMTV-Neu mice -a model driven by wild-type rat ERBB2 [69] -inhibition of the immunosuppressive enzyme indolamine 2,3-dioxygenase (IDO), cooperates with cisplatin, cyclophosphamide, doxorubicin and paclitaxel to retard tumor growth [70].…”

Section: Adaptive Immune Cellsmentioning

confidence: 99%

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

125

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SummaryConventional anti-cancer therapies, such as chemotherapy, radiotherapy and targeted therapy, are designed to kill cancer cells. Yet, the efficacy of anti-cancer therapies is not only determined by their direct effects on cancer cells, but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit a number of changes in immune-related parameters including the composition, phenotype and function of immune cells. In this review, we discuss the impact of innate and adaptive immune cells on the success of anti-cancer therapy, we examine the opportunities to exploit host immune responses to boost tumor clearing and we highlight the challenges facing the treatment of advanced metastatic disease. Then and now: The link between the immune system and anti-cancer therapiesThe relationship between anti-cancer therapies and the immune system is as old as the invention of anti-cancer therapies themselves. After the use of mustard gas in the trenches of World War I, a seminal observation was made that some exposed soldiers displayed severe loss of bone marrow and lymph node cells [1]. This observation then spurred the idea that the anti-proliferative capacity of mustard gas may also slow the growth of cancer cells.Experiments carried out in mice transplanted with lymphoid tumors were convincing enough to treat a lymphoma patient [2], and these events initiated the standardized treatment of cancer patients with chemotherapy [3,4].Fast forward 100 years later. The influence of immune cells on tumor progression and metastasis is well established [5], and an appreciation for the immune system's impact during conventional anti-cancer therapy treatment is growing. Recent seminal advances indicate that immune cells can shape the outcome of various anti-cancer therapies. As such, 2 immune cells and their molecular mediators have evolved into bona vide targets of therapeutic manipulation in cancer patients. The recent breakthrough of immunotherapeutics that inhibit negative immune regulatory pathways, such as anti-CTLA4 and anti-PD1, has initiated a new era in the treatment of cancer [6]. In parallel, immunomodulatory strategies aimed at dampening pro-tumor functions of immune cells are currently being tested in cancer patients [7]. Immune cells also function as reliable biomarkers, since their abundance or activation status often predicts how well patients respond to a particular treatment regimen.Here, we review these novel experimental and clinical insights, highlighting potential implications for the development of synergistic therapies designed to combat primary tumors and, more importantly, metastatic disease. The pros and cons of experimental mouse modelsResearch questions aimed at understanding the role of immune cells during anti-cancer therapy require models that mirror the complex interactions between the immune system and diverse forms of human cancers. Transplantable cancer cell line models and carcinogeninduced cancer models are the most frequently used for these purposes. However...

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Contribution of IL-17–producing γδ T cells to the efficacy of anticancer chemotherapy

Abstract: IL-17 production by γδ T cells is required for tumor cell infiltration by IFN-γ–producing CD8+ T cells and inhibition of tumor growth in response to anthracyclines.

Cited by 309 publications

References 56 publications

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

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Contribution of IL-17–producing γδ T cells to the efficacy of anticancer chemotherapy

Abstract: IL-17 production by γδ T cells is required for tumor cell infiltration by IFN-γ–producing CD8+ T cells and inhibition of tumor growth in response to anthracyclines.

Cited by 309 publications

References 56 publications

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

CCL25 induces α4β7 integrin‐dependent migration of IL‐17+γδ T lymphocytes during an allergic reaction

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

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CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction